Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors

ABSTRACT

Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/369,374 filed on Mar. 6, 2015, now U.S. Pat. No. 9,260,440, with thetitle “FUSED TETRA OR PENTA-CYCLIC DIHYDRODIAZEPINOCARBAZOLONES AS PARPINHIBITORS” which is a U.S. national stage application of InternationalApplication No. PCT/CN2011/085148, which was filed on Dec. 31, 2011 withthe title “FUSED TETRA OR PENTA-CYCLIC DIHYDRODIAZEPINOCARBAZOLONES ASPARP INHIBITORS”, the content of each of which are hereby incorporatedby reference in its entirety for all purposes.

Disclosed herein are fused tetra or penta-cyclic compounds which caninhibit the activity of poly (ADP-ribose)polymerases (PARPs),pharmaceutical compositions comprising at least one of the compounds,and the use thereof in treating certain diseases.

Poly(ADP-ribose) polymerases (PARPs), previously known aspoly(ADP-ribose) synthases or poly(ADP-ribose) transferases, are afamily of proteins that contain PARP catalytic domain (BMC Genomics,2005 Oct. 4; 6: 139). Approximately 17 members of PARPs have beendiscovered so far, including PARP-1, PARP-2, PARP-3, PARP-4(Vault-PARP),PARP-5a (Tankyrase-1), PARP5b (Tankyrase-2), PARP-6, PARP-7 (tiPARP),PARP-8, PARP-9 (BAL1), PARP-10, PARP-11, PARP-12, PARP-13 (ZAP), PARP-14(CoaSt6), PARP-15, and PARP-16. The catalytic activity of PARPs can beto transfer the ADP-ribose moiety from nicotinamide adenine dinucleotide(NAD⁺) to glutamic acid residues of a number of target proteins, and toform long branches of ADP-ribose polymers. However, some of the PARPfamilies have been reported to catalyze only mono-ADP-ribosylation oftargets while activities of others have yet to be reported (Mol. Cell.2008 Oct. 10; 32(1): 57-69). A number of the PARP enzymes have beenreported to show important functional roles in, for example, DNA repair,transcriptional regulation, mitotic progression, genomic integrity,telomere stability, cell death, and Wnt signaling pathway.

PARP-1 may be the most abundant and most well studied member of thefamily, and PARP-2 may be its closest relative. PARP can be activated bydamaged DNA fragments and, once activated, catalyzes the attachment ofpoly-ADP-ribose units to a variety of nuclear proteins, includinghistones and PARP itself. The resultant foci of poly(ADP-ribose) hasbeen reported to halt transcription and recruit repair enzymes to thesite of DNA damage. The pivotal role of PARP in the repair of DNA strandbreaks has been reported as well established. PARP-1 knockout cells canshow increased sensitivity to, for example, alkylating agents,topoisomerase (topo) I inhibitors and γ-irradiation. PARP inhibitorshave been reported to sensitize tumor cells to radiation treatment(including ionizing radiation and other DNA damaging treatments) andanticancer drugs (including platinum drugs, temozolomide, andtopoisomerase I inhibitors). PARP inhibitors have also been reported tobe effective in radiosensitizing (hypoxic) tumor cells and in preventingtumor cells from recovering from potentially lethal and sublethaldamages of DNA after radiation therapy, presumably by their ability toprevent broken DNA strand from rejoining and by affecting several DNAdamage signaling pathways.

PARP inhibitors have been suggested to effectively destroy tumorsdefective in the BRCA1 or BRCA2 genes through the concept of syntheticlethality. While tumors with wild type BRCA genes can be insensitive toPARP inhibitors, the presence of BRCA1 or BRCA2 deficiency leads tosignificantly increased sensitivity of those genes to PARP inhibitors.It can be suggested that PARP inhibitors may cause an increase in DNAsingle-strand breaks (SSBs), which are converted during replication totoxic DNA double-strand breaks (DSBs) that cannot be repaired byhomology recombination repair in BRCA1/2 defective cells. The syntheticlethality may have also been reported for PARP inhibitors, and ATM, ATR,RAD51 deficiency, and other homology recombination repair defects. PARPinhibitors can be useful for treatment of cancers with DNA repairdeficiencies.

Activation of PARP may also have a role in mediating cell death.Excessive activation of PARP may have been indicated inischemia-reperfusion injuries, and in neurological injuries that canoccur during stroke, trauma and Parkinson's disease. The overactivationof PARP may lead to rapid consumption of NAD⁺ to form ADP-ribosepolymers. Because the biosynthesis of NAD⁺ can be an ATP consumingprocess, the cellular level of ATP could be subsequently depleted andthe ischemic cells could die from necrosis. Inhibition of PARP can beexpected to reduce cell death by preserving cellular NAD⁺ and ATP leveland by preventing the activation of certain inflammation pathways thatcould have contributed to further cellular damage via an immuneresponse.

It has been reported that PARP activation can play a key role in bothNMDA- and NO-induced neurotoxicity. The reports were based on corticalcultures and hippocampal slices wherein prevention of toxicity can bedirectly correlated with PARP inhibition potency. The potential role ofPARP inhibitors in treating neurodegenerative diseases and head traumahas been hypothesized.

Studies have reported that PARP inhibitors can be used for treatment andprevention of autoimmune disease such as Type I diabetes and diabeticcomplications (Pharmaceutical Research (2005) 52: 60-71).

PARP-3 appears to be a newly characterized member of the PARP family. Arecent study has reported the role of PARP-3 in genome integrity andmitotic progression (PNAS|Feb. 15, 2011|vol. 108|no. 7|2783-2788).PARP-3 deficiency can lead to reduced cellular response to DNAdouble-strand breaks. PARP-3 deficiency when combined with PARP-1/2inhibitors can result in lowered cell survival in response tox-irradiation. PARP-3 can be required for mitotic spindle integrityduring mitosis and telomere stability. Therefore inhibition of PARP-3can also potentially lead to antitumor activity.

Tankyrase-1 (TRF1-interacting ankyrin-related ADP-ribosepolymerase 1) isinitially identified as a component of the human telomeric complex.Tankyrase-2 may share overall sequence identity of 83% and sequencesimilarity of 90% with Tankyrase-1. Mouse genetic studies reportedlysuggest substantial functional overlaps between tankyrase-1 andtankyrase-2. Tankyrase-1 has reportedly been shown to be a positiveregulator of telomere length, allowing elongation of the telomeres bytelomerase. Inhibition of tankyrases can sensitize cells to telomeraseinhibitors. Tankyrase-1 can be also required for sister telomeredissociation during mitosis. Inhibition of Tankyrase-1 by RNAi caninduce mitotic arrest. Inhibition of tankyrases potentially may lead toantitumor activity.

Tankyrases have reportedly been implicated in the regulation of Wntpathway. Wnt pathway can be negatively regulated by proteolysis of thedownstream effector β-catenin by the β-catenin destruction complex,comprising adenomatous polyposis coli (APC), axin and glycogen synthasekinase 3α/β (GSK3α/β). Inappropriate activation of the Wnt pathway hasbeen reported in many cancers. Notably, truncating mutations of thetumor suppressor APC can be the most prevalent genetic alterations incolorectal carcinomas. APC mutation may lead to defective β-catenindestruction complex, accumulation of nuclear β-catenin, and/or activetranscription of Wnt pathway-responsive genes. Tankyrase inhibitors havebeen reported to stabilize the β-catenin destruction complex byincreasing axin levels. Axin, a key component of β-catenin destructioncomplex, can be degraded through PARylation and ubiquitination.Inhibition of tankyrases can lead to reduced degradation of axin and/orincreased level of axin. Tankyrase inhibitors have been reported toinhibit colony formation by APC-deficient colon cancer cells. Therefore,tankyrase inhibitors can be potentially useful for treatment of cancerswith activated Wnt pathways.

Provided herein are compounds and/or pharmaceutically acceptable saltsthereof, pharmaceutical compositions comprising at least one of thosecompounds and pharmaceutically acceptable salts thereof, and use thereofin inhibiting PARP activity for treating diseases, such as cancer. Forexample, the compounds and compositions as described herein can beuseful in treating cancers with defective DNA repair pathways, and/orcan be useful in enhancing the effectiveness of chemotherapy andradiotherapy.

Certain small molecules have been reported to be PARP inhibitors. Forexample, PCT Publication Nos. WO 2000/42040 and 2004/800713 reporttricyclic indole derivatives as PARP inhibitors. PCT Publication Nos. WO2002/44183 and 2004/105700 report tricyclic diazepinoindole derivativesas PARP inhibitors; PCT Publication No. WO 2011/130661 and GB patent2462361 report dihydropyridophthalazinone derivatives as PARPinhibitors; other cyclic compounds reported as PARP inhibitors can befound in the following patents: U.S. Pat. No. 7,915,280; U.S. Pat. No.7,235,557; USRE041150; U.S. Pat. No. 6,887,996; and EP1339402B1.

PCT Publication No. WO 2004/4014294, published on Feb. 19, 2004 reports4,7-disubstituted indole derivatives as PARP inhibitors. Other cycliccompounds as PARP inhibitors are also reported in U.S. Pat. No.6,906,096. PCT Publication No. WO 2009/063244, published on May 22,2009, discloses pyridazinone derivatives as PARP inhibitors. GB PatentNo. 2462361, published on Oct. 2, 2010 disclosesdihydropyridophthalazinone derivatives as PARP inhibitors. U.S. Pat. No.7,429,578, published on Sep. 30, 2008, reports tricyclic derivatives asPARP inhibitors. Other cyclic compounds as PARP inhibitors are alsoreported in the following patents: EP1140936B1; U.S. Pat. No. 6,495,541;U.S. Pat. No. 6,799,298. U.S. Pat. No. 6,423,705, published on Jul. 23,2003, reports a combination therapy using PARP inhibitors. Othercombination therapies using PARP inhibitors are also reported in thefollowing patent publications: US 2009/0312280A1; WO 2007113647A1. U.S.Pat. No. 6,967,198, published on Nov. 22, 2005, reports tricycliccompounds as protein kinase inhibitors for enhancing efficacy ofantineoplastic agents and radiation therapy. U.S. Pat. No. 7,462,713,published on Dec. 9, 2008, also reports tricyclic compounds as proteinkinase inhibitors for enhancing efficacy of antineoplastic agents andradiation therapy. EP patent No. 1585749, published on Aug. 13, 2008,reports diazepinoindole derivatives as antineoplastic agents andradiation therapy.

Disclosed herein are compounds that can be poly(ADP-ribosyl)transferase(PARPs) inhibitors, and can be useful, for example, in treating cancers,stoke, head trauma, and neurodegenerative diseases. As cancertherapeutics, the compounds/pharmaceutically acceptable salts asdescribed herein may be used in combination with DNA-damaging cytotoxicagents, for example, cisplatin, topotecan, irinotecan, or temozolomide,and/or radiation.

Provided is at least one compound selected from comuounds of Formula(I):

stereoisomers thereof, and pharmaceutically acceptable salts thereof,

wherein:

R_(N) is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independentlyoptionally substituted with at least one substituent R¹²;

X is selected from the group consisting of C, N, O, and S;

m and n, which may be the same or different, are each an integer of 0,1, 2, or 3;

t is an integer of 0, 1, 2, or 3;

R¹, at each occurrence, is independently selected from halogen, CN, NO₂,OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰, NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹²;

R² is selected from hydrogen, COR⁹, CONR⁹R¹⁰, CO₂R⁹, SO₂R⁹, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹²;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸, which may be the same or different, are eachindependently selected from hydrogen, halogen —NR⁹R¹⁰, —OR⁹, oxo, —COR⁹,—CO²R⁹, —CONR⁹R¹⁰, —NR⁹CONR¹⁰R¹¹, —NR⁹CO₂R¹⁰, —NR⁹SO₂R¹⁰, —SO₂R⁹, alkyl,alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl is independently optionally substitutedwith at least one substituent R¹²,

or (R³ and R⁴), and/or (R⁴ and R⁵), and/or (R⁵ and R⁶), and/or (R⁶ andR⁷), and/or (R⁷ and R⁸), together with the atom(s) they are attached,form a 3- to 8-membered saturated, partially or fully unsaturated ringhaving 0, 1 or 2 heteroatoms independently selected from —NR¹³—, —O—,—S—, —SO— or —SO₂—, and said ring is optionally substituted with atleast one substituent R¹²,

provided that

-   -   when X is O, R⁵ and R⁶ are absent,    -   when X is N, R⁶ is absent,    -   when X is S, R⁵ and R⁶ are absent, or at least one of R⁵ and R⁶        is oxo,    -   when one of R³ and R⁴ is oxo, the other is absent,    -   when one of R⁷ and R⁸ is oxo, the other is absent, and    -   when X is C and one of R⁵ and R⁶ is oxo, the other is absent;

R⁹, R¹⁰, and R¹¹, which may be the same or different, are each selectedfrom hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl is independently optionallysubstituted with at least one substituent R¹²;

R¹² is selected from CN, halogen, haloalkyl, NO₂, —NR′R″, —OR′, oxo,—COR′, —CO₂R′, —CONR′R″, —NR′CONR″R′″, —NR′CO₂R″, —NR′SO₂R″, —SO₂R′,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein R′, R″, and R′″ are independently selected from hydrogen,haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl, or (R′ and R″), and/or (R″ and R′″) together withthe atoms to which they are attached, form a 3- to 8-membered saturated,partially or fully unsaturated ring having 0, 1 or 2 additionalheteroatoms independently selected from —NR¹³—, —O—, —S—, —SO— and—SO₂—.

R¹³ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl.

Also provided is a pharmaceutical composition comprising at least onepharmaceutically acceptable carrier and at least one compound selectedfrom compounds of Formula (I) and pharmaceutically acceptable saltsthereof as described herein.

Also provided is a method of inhibiting PARP comprising contacting thePARP with an amount of at least one compound selected from compounds ofFormula (I) and pharmaceutically acceptable salts thereof as describedherein effective to inhibit the PARP.

Also provided is a method of treating at least one disease responsive toinhibition of PARP comprising administering to a subject in recognizedneed of such treating for the at least one disease an amount of at leastone compound selected from compounds of Formula (I) and pharmaceuticallyacceptable salts thereof as described herein effective to treat the atleast one disease, wherein the at least one disease is selected from,for example, cancer (such as leukemia, colon cancer, glioblastomas,lymphomas, melanomas, carcinomas of the breast, and cervicalcarcinomas), cytotoxic cancer, ischemia reperfusion injury (such asthose associated with, but not limited to, heart failure, myocardialinfarction, stroke, other neural trauma, and organ transplantation),reperfusion (such as the reperfusion of the eye, kidney, gut andskeletal muscle), inflammatory diseases (such as arthritis, gout,inflammatory bowel disease, CNS inflammation, multiple sclerosis,allergic encephalitis, sepsis, septic shock, hemmorhagic shock,pulmonary fibrosis, and uveitis), immunological diseases or disorders(such as rheumatoid arthritis and septic shock), degenerative disease(such as diabetes and Parkinsons disease), hypoglycemia, retroviralinfection, liver toxicity following acetominophen overdose, cardiac andkidney toxicities from doxorubicin and platinum based antineoplasticagents, skin damage secondary to sulfur mustards.

Also provided is a use of at least one compound selected from compoundsof Formula (I) and pharmaceutically acceptable salts thereof asdescribed herein in manufacture of a medicament for inhibiting PARP.

Also provided is a use of at least one compound selected from compoundsof Formula (I) and pharmaceutically acceptable salts thereof asdescribed herein in the manufacture of a medicament for treating atleast one disease selected from, for example, cancer (such as leukemia,colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of thebreast, and cervical carcinomas), cytotoxic cancer, ischemia reperfusioninjury (such as those associated with, but not limited to, heartfailure, myocardial infarction, stroke, other neural trauma, and organtransplantation), reperfusion (such as the reperfusion of the eye,kidney, gut and skeletal muscle), inflammatory diseases (such asarthritis, gout, inflammatory bowel disease, CNS inflammation, multiplesclerosis, allergic encephalitis, sepsis, septic shock, hemmorhagicshock, pulmonary fibrosis, and uveitis), immunological diseases ordisorders (such as rheumatoid arthritis and septic shock), degenerativedisease (such as diabetes and Parkinsons disease), hypoglycemia,retroviral infection, liver toxicity following acetominophen overdose,cardiac and kidney toxicities from doxorubicin and platinum basedantineoplastic agents, skin damage secondary to sulfur mustards.

As used herein, the following words, phrases and symbols are generallyintended to have the meanings as set forth below, except to the extentthat the context in which they are used indicates otherwise. Thefollowing abbreviations and terms have the indicated meaningsthroughout:

The term “alkyl” herein refers to a hydrocarbon group selected fromlinear and branched saturated hydrocarbon groups comprising from 1 to18, such as from 1 to 12, further such as from 1 to 6, carbon atoms.Examples of the alkyl group can be selected from methyl, ethyl, 1-propylor n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl(“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl ors-butyl (“s-Bu”), and 1,1-dimethylethyl or t-butyl (“t-Bu”). Otherexamples of the alkyl group can be selected from 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂) and3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃ groups.

The term “alkenyl” herein refers to a hydrocarbon group selected fromlinear and branched hydrocarbon groups comprising at least one C═Cdouble bond and from 2 to 18, such as from 2 to 6, carbon atoms.Examples of the alkenyl group may be selected from ethenyl or vinyl(—CH═CH₂), prop-1-enyl (—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂),2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl,hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

The term “alkynyl” herein refers to a hydrocarbon group selected fromlinear and branched hydrocarbon group, comprising at least one CC triplebond and from 2 to 18, such as from 2 to 6, carbon atoms. Examples ofthe alkynyl group include ethynyl 1-propynyl (—C≡CCH₃), 2-propynyl(propargyl, —CH₂C≡CH), 1-butynyl, 2-butynyl, and 3-butynyl groups.

The term “cycloalkyl” herein refers to a hydrocarbon group selected fromsaturated and partially unsaturated cyclic hydrocarbon groups,comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic)groups. For example, the cycloalkyl group may comprise from 3 to 12,such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms.Even further for example, the cycloalkyl group may be selected frommonocyclic group comprising from 3 to 12, such as 3 to 8, 3 to 6 carbonatoms. Examples of the monocyclic cycloalkyl group include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, and cyclododecyl groups. Examples of thebicyclic cycloalkyl groups include those having from 7 to 12 ring atomsarranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and[6,6] ring systems, or as a bridged bicyclic ring selected frombicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.The ring may be saturated or have at least one double bond (i.e.partially unsaturated), but is not fully conjugated, and is notaromatic, as aromatic is defined herein.

The term “Aryl” herein refers to a group selected from:

-   -   5- and 6-membered carbocyclic aromatic rings, for example,        phenyl;    -   bicyclic ring systems such as 7 to 12 membered bicyclic ring        systems wherein at least one ring is carbocyclic and aromatic,        selected, for example, from naphthalene, indane, and        1,2,3,4-tetrahydroquinoline; and    -   tricyclic ring systems such as 10 to 15 membered tricyclic ring        systems wherein at least one ring is carbocyclic and aromatic,        for example, fluorene.

For example, the aryl group is selected from 5 and 6-memberedcarbocyclic aromatic rings fused to a 5- to 7-membered cycloalkyl orheterocyclic ring optionally comprising at least one heteroatom selectedfrom N, O, and S, provided that the point of attachment is at thecarbocyclic aromatic ring when the carbocyclic aromatic ring is fusedwith a heterocyclic ring, and the point of attachment can be at thecarbocyclic aromatic ring or at the cycloalkyl group when thecarbocyclic aromatic ring is fused with a cycloalkyl group. Bivalentradicals formed from substituted benzene derivatives and having the freevalences at ring atoms are named as substituted phenylene radicals.Bivalent radicals derived from univalent polycyclic hydrocarbon radicalswhose names end in “-yl” by removal of one hydrogen atom from the carbonatom with the free valence are named by adding “-idene” to the name ofthe corresponding univalent radical, e.g., a naphthyl group with twopoints of attachment is termed naphthylidene. Aryl, however, does notencompass or overlap in any way with heteroaryl, separately definedbelow. Hence, if one or more carbocyclic aromatic rings are fused with aheterocyclic aromatic ring, the resulting ring system is heteroaryl, notaryl, as defined herein.

The term “arylalkyl” herein refers to an alkyl group as defined abovesubstituted by an aryl group as defined above.

The term “halogen” or “halo” herein refers to F, Cl, Br or I.

The term “heteroaryl” herein refers to a group selected from:

-   -   5- to 7-membered aromatic, monocyclic rings comprising at least        one heteroatom, for example, from 1 to 4, or, in some        embodiments, from 1 to 3, heteroatoms, selected from N, O, and        S, with the remaining ring atoms being carbon;    -   8- to 12-membered bicyclic rings comprising at least one        heteroatom, for example, from 1 to 4, or, in some embodiments,        from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms,        selected from N, O, and S, with the remaining ring atoms being        carbon and wherein at least one ring is aromatic and at least        one heteroatom is present in the aromatic ring; and    -   11- to 14-membered tricyclic rings comprising at least one        heteroatom, for example, from 1 to 4, or in some embodiments,        from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms,        selected from N, O, and S, with the remaining ring atoms being        carbon and wherein at least one ring is aromatic and at least        one heteroatom is present in an aromatic ring.

For example, the heteroaryl group includes a 5- to 7-memberedheterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring.For such fused, bicyclic heteroaryl ring systems wherein only one of therings comprises at least one heteroatom, the point of attachment may beat the heteroaromatic ring or at the cycloalkyl ring.

When the total number of S and O atoms in the heteroaryl group exceeds1, those heteroatoms are not adjacent to one another. In someembodiments, the total number of S and O atoms in the heteroaryl groupis not more than 2. In some embodiments, the total number of S and Oatoms in the aromatic heterocycle is not more than 1.

Examples of the heteroaryl group include, but are not limited to, (asnumbered from the linkage position assigned priority 1) pyridyl (such as2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl,2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl,isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl,thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzoimidazolyl,indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl,pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl,pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl),pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl(such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl,1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl,1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl,1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, furopyridinyl, benzothiazolyl (such asbenzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and5,6,7,8-tetrahydroisoquinoline.

The term “heterocyclic” or “heterocycle” or “heterocyclyl” herein refersto a ring selected from 4- to 12-membered monocyclic, bicyclic andtricyclic, saturated and partially unsaturated rings comprising at leastone carbon atoms in addition to at least one heteroatom, such as from1-4 heteroatoms, further such as from 1-3, or further such as 1 or 2heteroatoms, selected from oxygen, sulfur, and nitrogen. “Heterocycle”herein also refers to a 5- to 7-membered heterocyclic ring comprising atleast one heteroatom selected from N, O, and S fused with 5-, 6-, and/or7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring,provided that the point of attachment is at the heterocyclic ring whenthe heterocyclic ring is fused with a carbocyclic aromatic or aheteroaromatic ring, and that the point of attachment can be at thecycloalkyl or heterocyclic ring when the heterocyclic ring is fused withcycloalkyl. “Heterocycle” herein also refers to an aliphatic spirocyclicring comprising at least one heteroatom selected from N, O, and S,provided that the point of attachment is at the heterocyclic ring. Therings may be saturated or have at least one double bond (i.e. partiallyunsaturated). The heterocycle may be substituted with oxo. The point ofthe attachment may be carbon or heteroatom in the heterocyclic ring. Aheterocycle is not a heteroaryl as defined herein.

Examples of the heterocycle include, but not limited to, (as numberedfrom the linkage position assigned priority 1) 1-pyrrolidinyl,2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl,2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl,azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl,dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl,piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl,thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl,1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepane1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl,dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl,1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl,dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl,1,1-dioxo-thiomorpholinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl and azabicyclo[2.2.2]hexanyl. A substitutedheterocycle also includes a ring system substituted with one or more oxomoieties, such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

Compounds described herein may contain an asymmetric center and may thusexist as enantiomers. Where the compounds described herein possess twoor more asymmetric centers, they may additionally exist asdiastereomers. Enantiomers and diastereomers fall within the broaderclass of stereoisomers. All such possible stereoisomers as substantiallypure resolved enantiomers, racemic mixtures thereof, as well as mixturesof diastereomers are intended to be included. All stereoisomers of thecompounds disclosed herein and/or pharmaceutically acceptable saltsthereof are intended to be included. Unless specifically mentionedotherwise, reference to one isomer applies to any of the possibleisomers. Whenever the isomeric composition is unspecified, all possibleisomers are included.

The term “substantially pure” as used herein means that the targetstereoisomer contains no more than 35%, such as no more than 30%,further such as no more than 25%, even further such as no more than 20%,by weight of any other stereoisomer(s). In some embodiments, the term“substantially pure” means that the target stereoisomer contains no morethan 10%, for example, no more than 5%, such as no more than 1%, byweight of any other stereoiosomer(s).

When compounds described herein contain olefinic double bonds, unlessspecified otherwise, such double bonds are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. For example,compounds including carbonyl —CH₂C(O)— groups (keto forms) may undergotautomerism to form hydroxyl —CH═C(OH)— groups (enol forms). Both ketoand enol forms, individually as well as mixtures thereof, are alsointended to be included where applicable.

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by the techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (“SMB”) and preparative thin or thick layer chromatography,as well as techniques of small scale thin layer and flashchromatography. One skilled in the art will apply techniques most likelyto achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., a substantially pure enantiomer, may beobtained by resolution of the racemic mixture using a method such asformation of diastereomers using optically active resolving agents(Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York:John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al.“Chromatographic resolution of enantiomers: Selective review.” J.Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: Wainer,Irving W., Ed. Drug Stereochemistry: Analytical Methods andPharmacology. New York: Marcel Dekker, Inc., 1993.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, selected, for example, from hydrochlorates,phosphates, diphosphates, hydrobromates, sulfates, sulfinates, andnitrates; as well as salts with organic acids, selected, for example,from malates, maleates, fumarates, tartrates, succinates, citrates,lactates, methanesulfonates, p-toluenesulfonates,2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkanoatessuch as acetate, and salts with HOOC—(CH₂)_(n)—COOH, wherein n isselected from 0 to 4. Similarly, examples of pharmaceutically acceptablecations include, but are not limited to, sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if a compound disclosed herein is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, such as a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used without undue experimentation to prepare non-toxicpharmaceutically acceptable addition salts.

As defined herein, “pharmaceutically acceptable salts thereof” includesalts of at least one compound of Formulas I, II (including II-1, II-2or II-3) or III, and salts of the stereoisomers of at least one compoundof Formulas I, II (including II-1, II-2 or II-3) or III, such as saltsof enantiomers, and/or salts of diastereomers.

“Treating”, “treat”, or “treatment” or “alleviation” refers toadministering at least one compound and/or at least one pharmaceuticallyacceptable salt thereof disclosed herein to a subject in recognized needthereof that has, for example, cancer and/or inflammatory disease, orhas a symptom of, for example, cancer and/or inflammatory disease, orhas a predisposition toward, for example, cancer and/or inflammatorydisease, with the purpose to cure, heal, alleviate, relieve, alter,remedy, ameliorate, improve, or affect, for example, cancer and/orinflammatory disease, the symptoms of, for example, cancer and/orinflammatory disease, or the predisposition toward, for example, cancerand/or inflammatory disease.

The term “effective amount” refers to an amount of at least onecompound, stereoisomers thereof, and pharmaceutically acceptable saltsthereof disclosed herein effective to “treat,” as defined above, adisease or disorder in a subject. In the case of cancer, the effectiveamount may cause any of the changes observable or measurable in asubject as described in the definition of “treating,” “treat,”“treatment” and “alleviation” above. For example, the effective amountcan reduce the number of cancer or tumor cells; reduce the tumor size;inhibit or stop tumor cell infiltration into peripheral organsincluding, for example, the spread of tumor into soft tissue and bone;inhibit and stop tumor metastasis; inhibit and stop tumor growth;relieve to some extent one or more of the symptoms associated with thecancer, reduce morbidity and mortality; improve quality of life; or acombination of such effects. An effective amount may be an amountsufficient to decrease the symptoms of a disease responsive toinhibition of PARP. For cancer therapy, efficacy in vivo can, forexample, be measured by assessing the duration of survival, time todisease progression (TTP), the response rates (RR), duration ofresponse, and/or quality of life. Effective amounts may vary, asrecognized by those skilled in the art, depending on route ofadministration, excipient usage, and co-usage with other agents.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of PARP” refers to adecrease in the activity of PARP as a direct or indirect response to thepresence of at least one compound and/or at least one pharmaceuticallyacceptable salt disclosed herein, relative to the activity of PARP inthe absence of the at least one compound and/or the at least onepharmaceutically acceptable salt thereof. The decrease in activity isnot bound by theory and may be due to the direct interaction of the atleast one compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof disclosed herein with PARP, or due to theinteraction of the at least one compound and/or at least onepharmaceutically acceptable salt disclosed herein, with one or moreother factors that in turn affect PARP activity. For example, thepresence of at least one compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof disclosed herein, may decreasePARP activity by directly binding to the PARP, by causing (directly orindirectly) another factor to decrease PARP activity, or by (directly orindirectly) decreasing the amount of PARP present in the cell ororganism.

The term “at least one substituent” disclosed herein includes, forexample, from 1 to 4, such as from 1 to 3, further as 1 or 2,substituents. For example, “at least one substituent R¹²” disclosedherein includes from 1 to 4, such as from 1 to 3, further as 1 or 2,substituents selected from the list of R¹² as described herein.

In the first aspect, provided is at least one compound selected fromcompounds of Formula (I):

stereoisomers thereof, and pharmaceutically acceptable salts thereof,wherein:

R_(N) is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independentlyoptionally substituted with at least one substituent R¹²;

X is selected from the group consisting of C, N, O, and S;

m and n, which may be the same or different, are each an integer of 0,1, 2, or 3;

t is an integer of 0, 1, 2, or 3;

R¹, at each occurrence, is independently selected from halogen, CN, NO₂,OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰, NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹²;

R² is selected from the group consisting of hydrogen, COR⁹, CONR⁹R¹⁰,CO₂R⁹, SO₂R⁹, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl is independently optionallysubstituted with at least one substituent R¹²;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸, which may be the same or different, are eachindependently selected from absence, hydrogen, halogen, —NR⁹R¹⁰, OR⁹,oxo, —COR⁹, —CO₂R⁹, —CONR⁹R¹⁰, —NR⁹CONR¹⁰R¹¹, NR⁹CO₂R¹⁰, —NR⁹SO₂R¹⁰,—SO₂R⁹, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, andheteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heterocyclyl, and heteroaryl is independently optionallysubstituted with at least one substituent R¹²,

or (R³ and R⁴), and/or (R⁴ and R⁵), and/or (R⁵ and R⁶), and/or (R⁶ andR⁷), and/or (R⁷ and R⁸), together with the atom(s) they are attached,form a 3- to 8-membered saturated, partially or fully unsaturated ringhaving 0, 1 or 2 heteroatoms independently selected from —NR¹³—, —O—,—S—, —SO— or —SO₂—, and said ring is optionally substituted with atleast one substituent R¹²,

provided that

-   -   when X is O, R⁵ and R⁶ are absent,    -   when X is N, R⁶ is absent,    -   when X is S, R⁵ and R⁶ are absent, or at least one of R⁵ and R⁶        is oxo,    -   when one of R³ and R⁴ is oxo, the other is absent,    -   when one of R⁷ and R⁸ is oxo, the other is absent, and    -   when X is C and one of R⁵ and R⁶ is oxo, the other is absent;

R⁹, R¹⁰, and R¹¹, which may be the same or different, are each selectedfrom hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl is independently optionallysubstituted with at least one substituent R¹²;

R¹² is selected from CN, halogen, haloalkyl, NO₂, —NR′R″, —OR′, oxo,—COR′, —CO₂R′, —CONR′R″, —NR′CONR″R′″, —NR′CO₂R″, —NR′SO₂R″, —SO₂R′,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein R′, R″, and R′″ are independently selected from hydrogen,haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl, or (R′ and R″), and/or (R″ and R′″) together withthe atoms to which they are attached, form a 3- to 8-membered saturated,partially or fully unsaturated ring having 0, 1 or 2 additionalheteroatoms independently selected from —NR¹³—, —O—, —S—, —SO— and—SO₂—.

R¹³ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl.

In some embodiments, X in Formula (I) is C. In some embodiments, X inFormula (I) is N.

In some embodiments, m and n in Formula (I) are both an integer of 1. Insome embodiments, n in Formula (I) is 1 and m in Formula (I) is 2; inother embodiments, n in Formula (I) is 2 and m in Formula (I) is 1.

In some embodiments, t in Formula (I) is 0. In some embodiments, t inFormula (I) is 1 and R¹ in Formula (I) is selected from halogen, CN,NO₂, OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰, NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl is independently optionally substituted with atleast one substituent R¹² as defined above. In some further embodiments,t in Formula (I) is 1, and R¹ in Formula (I) is halogen (such as F, Cland Br, further such as F) or alkyl (such as C₁₋₁₂alkyl, further such asC₁₋₆alkyl). In some further embodiments, t in Formula (I) is 1 and R¹ inFormula (I) is halogen (such as F).

In some embodiments, R_(N) in Formula (I) is an alkyl group optionallysubstituted with hydroxy or alkoxyl. In some further embodiments, R_(N)in Formula (I) is a C₁₋₁₂alkyl group optionally substituted with hydroxyor with C₁₋₁₂alkoxyl. In some further embodiments, R_(N) in Formula (I)is a C₁₋₆alkyl group optionally substituted with hydroxy or withC₁₋₆alkoxyl.

In some embodiments, R² in Formula (I) is hydrogen or alkyl (such asC₁₋₁₂alkyl, further such as C₁₋₆alkyl) optionally substituted with atleast one substituent R¹² as defined for Formula (I). In someembodiments, R² in Formula (I) is alkyl (such as C₁₋₁₂alkyl, furthersuch as C₁₋₆alkyl) optionally substituted with at least one substituentR¹², wherein R¹² is selected from —NR′R″, —OR′, heterocyclyl, and aryl,wherein R′, and R″ are independently selected from hydrogen, haloalkyl,alkyl, and arylalkyl, or R′ and R″ together with the atom to which theyare attached, form a 3- to 8-membered saturated, partially or fullyunsaturated ring having 0, 1 or 2 additional heteroatoms independentlyselected from —NR¹³—, —O—, —S—, —SO— and —SO₂—. In some furtherembodiments, R² in Formula (I) is an alkyl group (such as C₁₋₁₂alkyl,further such as C₁₋₆alkyl) optionally substituted with at least onesubstituent R¹², wherein R¹² is selected from —NR′R″, —OR′,heterocyclyl, and aryl (such as phenyl), wherein R′ and R″ areindependently selected from hydrogen, haloalkyl (such as haloC₁₋₁₂alkyl,further such as haloC₁₋₆alkyl), alkyl (such as C₁₋₁₂alkyl, further suchas C₁₋₆alkyl), and arylalkyl (such as phenylC₁₋₁₂alkyl, further such asphenylC₁₋₆alkyl)), or R′ and R″ together with the atom to which they areattached, form a 3- to 8-membered saturated, partially or fullyunsaturated ring having 0, 1 or 2 additional heteroatoms independentlyselected from —NR¹³—, —O—, —S—, —SO— and —SO₂— (such as a 5- or6-membered saturated ring having 0 or 1 additional heteroatom which isO, further such as 5-membered saturated ring, 6-membered saturated ring,or 6-membered saturated ring having one oxygen heteroatom). In somefurther embodiments, R² in Formula (I) is alkyl (such as C₁₋₁₂alkyl,further such as C₁₋₆alkyl) optionally substituted with at least onesubstituent selected from an aryl group (such as phenyl), 3-, 4-, 5-,6-, 7-, and 8-membered heterocyclyl group containing one nitrogenheteroatom and/or one oxygen heteroatom, —OR′, and —NR′R″, wherein R′and R″ are independently selected from hydrogen, haloalkyl (such ashaloC₁₋₁₂alkyl, further such as haloC₁₋₆alkyl), alkyl (such asC₁₋₁₂alkyl, further such as C₁₋₆alkyl), and arylalkyl (such asphenylC₁₋₆alkyl). In some further embodiments, R² in Formula (I) isalkyl (such as C₁₋₁₂alkyl, further such as C₁₋₆alkyl) optionallysubstituted with at least one substituent selected from an aryl group(such as phenyl); 3-, 4-, 5-, 6-, 7-, and 8-membered heterocyclyl groupcontaining one nitrogen heteroatom and/or one oxygen heteroatom selectedfrom pyrrolidinyl, piperidinyl, morpholino, and oxiranyl; —OR′; and—NR′R″, wherein R′ and R″ are independently selected from the hydrogen,haloalkyl (such as haloC₁₋₆alkyl), alkyl (such as C₁₋₁₂alkyl, furthersuch as C₁₋₆alkyl), and arylalkyl (such as phenylC₁₋₆alkyl, further suchas phenylmethyl).

In some embodiments, R⁵ in Formula (I) is selected from hydrogen, alkyl,cycloalkyl, aryl, —COR⁹, and —COOR⁹, wherein each of the alkyl,cycloalkyl, and aryl is independently optionally substituted with atleast one substituent R¹², and R⁹ is alkyl or cycloalkyl optionallysubstituted with at least one substituent R¹², and R¹² is defined as forFormula (I). In some embodiments, R⁵ in Formula (I) is selected fromhydrogen, alkyl, cycloalkyl, aryl, —COR⁹, and —COOR⁹, wherein each ofthe alkyl, cycloalkyl, or aryl is independently optionally substitutedwith at least one substituent R¹², and R⁹ is alkyl or cycloalkyloptionally substituted with at least one substituent R¹², and R¹² isselected from NR′R″, aryl, and NR′CO₂R″, wherein R′ and R″ areindependently selected from hydrogen, haoloalkyl and alkyl. In somefurther embodiments, R⁵ in Formula (I) is selected from hydrogen; alkyl(such as C₁₋₁₂alkyl, further such as C₁₋₆alkyl) optionally substitutedwith at least one substituent selected from NR′R″ and aryl (such asphenyl); cycloalkyl (such as C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl); aryl(such as phenyl) optionally substituted with NR′R″; and —COR⁹, whereinR⁹ is cycloalkyl (such as C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl), or alkyl(such as C₁₋₁₂alkyl, further such as C₁₋₆alkyl), each of the cycloalklyand alkyl is optionally substituted with at least one substituentselected from NR′R″, aryl (such as phenyl), and —NR′CO₂R″, wherein R′and R″ are independently selected from hydrogen, haloalkyl (such ashaloC₁₋₆alkyl), and alkyl (such as C₁₋₆alkyl). In some furtherembodiments, R⁵ in Formula (I) is selected from hydrogen; C₁₋₆alkyl(such as methyl, ethyl, propyl, isopropyl, butyl, or 3,3-dimethylbutyl)optionally substituted with NR′R″; cyclohexyl; phenyl optionallysubstituted with NR′R″; and —COR⁹, wherein R⁹ is cyclopropyl, orC₁₋₆alkyl (such as methyl, ethyl, propyl, isopropyl, or butyl), each ofthe cyclopropyl and C₁₋₆alkyl is optionally substituted with at leastone substituent selected from NR′R″, aryl (such as phenyl) and—NR′CO₂R″, wherein R′ and R″ are independently selected from hydrogenand C₁₋₆alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, ortert-butyl).

In some embodiments, R⁴ and R⁵ in Formula (I), together with the atomsto which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-memberedsaturated, partially or fully unsaturated ring having 0, 1 or 2heteroatoms independently selected from —NR¹³—, —O—, —S—, —SO— and—SO₂—, and said ring is optionally substituted with at least onesubstituent R′² as defined for Formula (I). In some embodiments, R⁴ andR⁵ in Formula (I), together with the atoms to which they are attached,form a 5-membered saturated ring having one nitrogen heteroatom.

In some embodiments, at least one pair of (R³ and R⁴), (R⁵ and R⁶), and(R⁷ and R⁸) in Formula (I) are alkyl (such as C₁₋₁₂alkyl, further suchas C₁₋₆alkyl, further such as methyl). In some embodiments, R³ and R⁴ inFormula (I), which may be the same or different, are each independentlyselected from hydrogen, alkyl (such as C₁₋₁₂alkyl, further such asC₁₋₆alkyl) and OH.

In the second aspect, the at least one compound selected from compoundsof Formula (I), stereoisomers thereof, and pharmaceutically acceptablesalts thereof is selected from the compounds of Formula (II) below:

stereoisomers thereof, and pharmaceutically acceptable salts thereof,wherein:

R_(N) is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independentlyoptionally substituted with at least one substituent R¹²;

m and n, which may be the same or different, are each an integer of 0,1, 2, or 3;

t is an integer of 0, 1, 2, or 3;

R¹, at each occurrence, is independently selected from halogen, CN, NO₂,OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰, NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹²;

R² is selected from hydrogen, COR⁹, CONR⁹R¹⁰, CO₂R⁹, SO₂R⁹, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹²;

R³, R⁴, R⁵, R⁶, R⁷ and R⁸, which may be the same or different, are eachindependently selected from hydrogen, halogen, —NR⁹R¹⁰, —OR⁹, oxo,—COR⁹, —CO₂R⁹, —CONR⁹R¹⁰, —NR⁹CONR¹⁰R¹¹, —NR⁹CO₂R¹⁰, —NR⁹SO₂R¹⁰, —SO₂R⁹,alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl is independently optionally substitutedwith at least one substituent R¹², or (R³ and R⁴), and/or (R⁴ and R⁵),and/or (R⁵ and R⁶), and/or (R⁶ and R⁷), and/or (R⁷ and R⁸), togetherwith the atom(s) to which they are attached, form a 3- to 8-memberedsaturated, partially or fully unsaturated ring having 0, 1 or 2heteroatoms independently selected from —NR¹³—, —O—, —S—, —SO— and—SO₂—, and said ring is optionally substituted with at least onesubstituent R¹², provided that

-   -   when one of R³ and R⁴ is oxo, the other is absent,    -   when one of R⁷ and R⁸ is oxo, the other is absent, and    -   when one of R⁵ and R⁶ is oxo, the other is absent;

R⁹, R¹⁰, and R¹¹, which may be the same or different, are each selectedfrom hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl is independently optionallysubstituted with at least one substituent R¹²;

R¹² is selected from CN, halogen, haloalkyl, NO₂, —NR′R″, —OR′, oxo,—COR′, —CO₂R′, —CONR′R″, —NR′CONR″R′″, —NR′CO₂R″, —NR′SO₂R″, —SO₂R′,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein R′, R″, and R′″ are independently selected from hydrogen,haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl, or (R′ and R″), and/or (R″ and R′″) together withthe atoms to which they are attached, form a 3- to 8-membered saturated,partially or fully unsaturated ring having 0, 1 or 2 additionalheteroatoms independently selected from —NR¹³—, —O—, —S—, —SO— or —SO₂—.

R¹³ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl.

In some embodiments, m and n in Formula (II) are both an integer of 1.In some embodiments, n in Formula (II) is 1 and m in Formula (II) is 2;in other embodiments, n in Formula (II) is 2 and m in Formula (II) is 1.

In some embodiments, t in Formula (II) is 0. In some embodiments, t inFormula (II) is 1 and R¹ in Formula (II) is selected from halogen, CN,NO₂, OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰, NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹² as defined above. In some further embodiments,t in Formula (II) is 1, and R¹ in Formula (II) is halogen (such as F, Cland Br, further such as F) or alkyl (such as C₁₋₁₂alkyl, further such asC₁₋₆alkyl). In some further embodiments, t in Formula (II) is 1, and R¹in Formula (II) is halogen (such as F).

In some embodiments, R_(N) in Formula (II) is an alkyl group optionallysubstituted with at least one substituent selected from hydroxy andalkoxyl. In some further embodiments, R_(N) in Formula (II) is aC₁₋₁₂alkyl group optionally substituted with at least one substituentselected from hydroxy and C₁₋₁₂alkoxyl. In some further embodiments,R_(N) in Formula (II) is a C₁₋₆alkyl group optionally substituted withat least one substituent selected from hydroxy and C₁₋₆alkoxyl.

In some embodiments, R² in Formula (II) is hydrogenor alkyl (such asC₁₋₁₂alkyl, further such as C₁₋₆alkyl) optionally substituted with atleast one substituent R¹² as defined for Formula (II). In someembodiments, R² in Formula (II) is alkyl (such as C₁₋₁₂alkyl, furthersuch as C₁₋₆alkyl) optionally substituted with at least one substituentR¹², wherein R¹² is selected from —NR′R″, —OR′, heterocyclyl, and aryl,wherein R′, and R″ are independently selected from hydrogen, haloalkyl,alkyl, and arylalkyl, or R′ and R″ together with the atom to which theyare attached, form a 3- to 8-membered saturated, partially or fullyunsaturated ring having 0, 1 or 2 additional heteroatoms independentlyselected from —NR¹³—, —O—, —S—, —SO— and —SO₂—. In some furtherembodiments, R² in Formula (II) is alkyl (such as C₁₋₁₂alkyl, furthersuch as C₁₋₆alkyl) optionally substituted with at least one substituentR¹², wherein R¹² is selected from —NR′R″, —OR′, heterocyclyl, and aryl(such as phenyl), wherein R′ and R″ are independently selected fromhydrogen, haloalkyl (such as haloC₁₋₁₂alkyl, further such ashaloC₁₋₆alkyl), alkyl (such as C₁₋₁₂alkyl, further such as C₁₋₆alkyl),and arylalkyl (such as phenylC₁₋₁₂alkyl, further such asphenylC₁₋₆alkyl)), or R′ and R″ together with the atom to which they areattached, form a 3- to 8-membered saturated, partially or fullyunsaturated ring having 0, 1 or 2 additional heteroatoms independentlyselected from —NR¹³—, —O—, —S—, —SO— and —SO₂— (such as a 5- or6-membered saturated ring having 0 or 1 additional heteroatom which isO, further such as 5-membered saturated ring, 6-membered saturated ring,or 6-membered saturated ring having one oxygen heteroatom). In somefurther embodiments, R² in Formula (II) is alkyl (such as C₁₋₁₂alkyl,further such as C₁₋₆alkyl) optionally substituted with at least onesubstituent selected from aryl (such as phenyl), 3-, 4-, 5-, 6-, 7-, and8-membered heterocyclyl containing one nitrogen heteroatom and/or oneoxygen heteroatom, —OR′, and —NR′R″, wherein R′ and R″ are independentlyselected from hydrogen, haloalkyl (such as haloC₁₋₁₂alkyl, further suchas haloC₁₋₆alkyl), alkyl (such as C₁₋₁₂alkyl, further such asC₁₋₆alkyl), and arylalkyl (such as phenylC₁₋₆alkyl). In some furtherembodiments, R² in Formula (II) is alkyl (such as C₁₋₁₂alkyl, furthersuch as C₁₋₆alkyl) optionally substituted with at least one substituentselected from aryl (such as phenyl); 3-, 4-, 5-, 6-, 7-, and 8-memberedheterocyclyl group containing one nitrogen heteroatom and/or one oxygenheteroatom selected from pyrrolidinyl, piperidinyl, morpholino, andoxiranyl; —OR′; and —NR′R″, wherein R′ and R″ are independently selectedfrom hydrogen, haloalkyl (such as haloC₁₋₆alkyl), alkyl (such asC₁₋₁₂alkyl, further such as C₁₋₆alkyl), and arylalkyl (such asphenylC₁₋₆alkyl, further such as phenylmethyl).

In some embodiments, R⁵ in Formula (II) is selected from hydrogen,alkyl, cycloalkyl, aryl, —COR⁹, and —COOR⁹, wherein each of the alkyl,cycloalkyl, and aryl is independently optionally substituted with atleast one substituent R¹², and R⁹ is alkyl or cycloalkyl optionallysubstituted with at least one substituent R¹², and R¹² is defined as forFormula (II). In some embodiments, R⁵ in Formula (II) is selected fromhydrogen, alkyl, cycloalkyl, aryl, —COR⁹, and —COOR⁹, wherein each ofthe alkyl, cycloalkyl, and aryl is independently optionally substitutedwith at least one substituent R¹², and R⁹ is alkyl or cycloalkyloptionally substituted with at least one substituent R¹², and R¹² isselected from NR′R″, aryl, and NR′CO₂R″, wherein R′ and R″ areindependently selected from hydrogen, haoloalkyl and alkyl. In somefurther embodiments, R⁵ in Formula (II) is selected from hydrogen; alkyl(such as C₁₋₁₂alkyl, further such as C₁₋₆alkyl) optionally substitutedwith at least one substituent selected from NR′R″ and aryl (such asphenyl); cycloalkyl (such as C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl); aryl(such as phenyl) optionally substituted with NR′R″; and —COR⁹, whereinR⁹ is cycloalkyl (such as C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl), or alkyl(such as C₁₋₁₂alkyl, further such as C₁₋₆alkyl), each of the cycloalkyland alkyl is optionally substituted with at least one substituentselected from NR′R″, aryl (such as phenyl), and —NR′CO₂R″, wherein R′and R″ are independently selected from hydrogen, haloalkyl (such ashaloC₁₋₆alkyl), and alkyl (such as C₁₋₆alkyl). In some furtherembodiments, R⁵ in Formula (II) is selected from hydrogen; C₁₋₆alkyl(such as methyl, ethyl, propyl, isopropyl, butyl, or 3,3-dimethylbutyl)optionally substituted with NR′R″; cyclohexyl; phenyl optionallysubstituted with NR′R″; and —COR⁹, wherein R⁹ is cyclopropyl, orC₁₋₆alkyl (such as methyl, ethyl, propyl, isopropyl, or butyl), each ofthe cyclopropyl and C₁₋₆alkyl is optionally substituted with at leastone substituent selected from NR′R″, aryl (such as phenyl), and—NR′CO₂R″, wherein R′ and R″ are independently selected from hydrogenand C₁₋₆alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, ortert-butyl).

In some embodiments, R⁴ and R⁵ in Formula (II), together with theatom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7- or8-membered saturated, partially or fully unsaturated ring having 0, 1 or2 heteroatoms independently selected from —NR¹³—, —O—, —S—, —SO— and—SO₂—, and said ring is optionally substituted with at least onesubstituent R′² as defined for Formula (II). In some furtherembodiments, R⁴ and R⁵ in Formula (II), together with the atom(s) towhich they are attached, form a 5-membered saturated ring having onenitrogen heteroatom.

In some embodiments, at least one pair of (R³ and R⁴), (R⁵ and R⁶), and(R⁷ and R⁸) in Formula (II) are alkyl (such as C₁₋₁₂alkyl, further suchas C₁₋₆alkyl, further such as methyl). In some embodiments, R³ and R⁴ inFormula (II), which may be the same different, are each independentlyselected from hydrogen, alkyl (such as C₁₋₁₂alkyl, further such asC₁₋₆alkyl) and OH.

In the third aspect, the at least one compound selected from compoundsof Formula (I), stereoisomers thereof, and pharmaceutically acceptablesalts thereof is selected from the compounds of Formula (III) below:

stereoisomers thereof, and pharmaceutically acceptable salts thereof,wherein:

R_(N) is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independentlyoptionally substituted with at least one substituent R¹²;

m and n, which may be the same or different, are each an integer of 0,1, 2, or 3;

t is an integer of 0, 1, 2, or 3;

R¹, at each occurrence, is independently selected from halogen, CN, NO₂,OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰, NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹²;

R² is selected from hydrogen, COR⁹, CONR⁹R¹⁰, CO₂R⁹, SO₂R⁹, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹²;

R³, R⁴, R⁵, R⁷ and R⁸, which may be the same or different, are eachindependently selected from hydrogen, halogen, —NR⁹R¹⁰, —OR⁹, oxo,—COR⁹, —CO₂R⁹, CONR⁹R¹⁰, —NR⁹CONR¹⁰R¹¹, —NR⁹CO₂R¹⁰, —NR⁹SO₂R¹⁰, —SO₂R⁹,alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl is independently optionally substitutedwith at least one substituent R¹², or (R³ and R⁴), and/or (R⁴ and R⁵),and/or (R⁵ and R⁷), and/or (R⁷ and R⁸), together with the atom(s) theyare attached, form a 3- to 8-membered saturated, partially or fullyunsaturated ring having 0, 1 or 2 heteroatoms independently selectedfrom —NR¹³—, —O—, —S—, —SO—, and —SO₂—, and said ring is optionallysubstituted with at least one substituent R¹²,

provided that

-   -   when one of R³ and R⁴ is oxo, the other is absent, and        -   when one of R⁷ and R⁸ is oxo, the other is absent; R⁹, R¹⁰,            and R¹¹, which may be the same or different, are each            selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,            heterocyclyl, aryl, and heteroaryl, wherein each of the            alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and            heteroaryl is independently optionally substituted with at            least one substituent R¹²;

R¹² is selected from CN, halogen, haloalkyl, NO₂, —NR′R″, —OR′, oxo,—COR′, —CO₂R′, —CONR′R″, —NR′CONR″R′″, —NR′CO₂R″, —NR′SO₂R″, —SO₂R′,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein R′, R″, and R′″ are independently selected from hydrogen,haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl, or (R′ and R″), and/or (R″ and R′″) together withthe atoms to which they are attached, form a 3- to 8-membered saturated,partially or fully unsaturated ring having 0, 1 or 2 additionalheteroatoms independently selected from —NR¹³—, —O—, —S—, —SO— or —SO₂—;and

R¹³ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl.

In some embodiments, m and n in Formula (III) are both an integer of 1.In some embodiments, n in Formula (III) is 1, and m in Formula (III) is2; in other embodiments, n in Formula (III) is 2, and m in Formula (III)is 1.

In some embodiments, t in Formula (III) is 0. In some embodiments, t inFormula (III) is 1, and R¹ in Formula (III) is selected from halogen,CN, NO₂, OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰, NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹² as defined above. In some further embodiments,t in Formula (III) is 1, and R¹ in Formula (III) is halogen (such as F,Cl and Br, further such as F) or alkyl (such as C₁₋₁₂alkyl, further suchas C₁₋₆alkyl). In some further embodiments, t in Formula (III) is 1, andR¹ in Formula (III) is halogen (such as F).

In some embodiments, R_(N) in Formula (III) 15 alkyl optionallysubstituted with at least one substituent selected from hydroxy andalkoxyl. In some further embodiments, R_(N) in Formula (III) is aC₁₋₁₂alkyl optionally substituted with at least one substituent selectedfrom hydroxy and C₁₋₁₂alkoxyl. In some further embodiments, R_(N) inFormula (III) is a C₁₋₆alkyl group optionally substituted with at leastone substituent selected from hydroxy and C₁₋₆alkoxyl.

In some embodiments, R² in Formula (III) 15 hydrogenor alkyl (such asC₁₋₁₂alkyl, further such as C₁₋₆alkyl) optionally substituted with atleast one substituent R¹² as defined for Formula (III). In someembodiments, R² in Formula (III) is alkyl (such as C₁₋₁₂alkyl, furthersuch as C₁₋₆alkyl) optionally substituted with at least one substituentR¹², wherein R¹² is selected from —NR′R″, —OR′, heterocyclyl, and aryl,wherein R′ and R″ are each independently selected from hydrogen,haloalkyl, alkyl, and arylalkyl, or R′ and R″ together with the atom towhich they are attached, form a 3- to 8-membered saturated, partially orfully unsaturated ring having 0, 1 or 2 additional heteroatomsindependently selected from —NR¹³—, —O—, —S—, —SO—, and —SO₂—. In somefurther embodiments, R² in Formula (III) is alkyl (such as C₁₋₁₂alkyl,further such as C₁₋₆alkyl) optionally substituted with at least onesubstituent R¹², wherein R¹² is selected from —NR′R″, —OR′,heterocyclyl, and aryl (such as phenyl), wherein R′ and R″ areindependently selected from hydrogen, haloalkyl (such as haloC₁₋₁₂alkyl,further such as haloC₁₋₆alkyl), alkyl (such as C₁₋₁₂alkyl, further suchas C₁₋₆alkyl), and arylalkyl (such as phenylC₁₋₁₂alkyl, further such asphenylC₁₋₆alkyl)), or R′ and R″ together with the atom to which they areattached, form a 3- to 8-membered saturated, partially or fullyunsaturated ring having 0, 1 or 2 additional heteroatoms independentlyselected from —NR¹³—, —O—, —S—, —SO— or —SO₂— (such as a 5- or6-membered saturated ring having 0 or 1 additional heteroatom which isO, further such as 5-membered saturated ring, 6-membered saturated ring,or 6-membered saturated ring having one oxygen heteroatom). In somefurther embodiments, R² in Formula (III) is alkyl (such as C₁₋₁₂alkyl,further such as C₁₋₆alkyl) optionally substituted with at least onesubstituent selected from aryl (such as phenyl), 3-, 4-, 5-, 6-, 7-, and8-membered heterocyclyl group containing one nitrogen heteroatom and/orone oxygen heteroatom, —OR′, and —NR′R″, wherein R′ and R″ areindependently selected from hydrogen, haloalkyl (such as haloC₁₋₁₂alkyl,further such as haloC₁₋₆alkyl), alkyl (such as C₁₋₁₂alkyl, further suchas C₁₋₆alkyl), and arylalkyl (such as phenylC₁₋₆alkyl). In some furtherembodiments, R² in Formula (III) is an alkyl (such as C₁₋₁₂alkyl,further such as C₁₋₆alkyl) optionally substituted with at least onesubstituent selected from aryl (such as phenyl); 3-, 4-, 5-, 6-, 7-, and8-membered heterocyclyl group containing one nitrogen heteroatom and/orone oxygen heteroatom selected from pyrrolidinyl, piperidinyl,morpholino, and oxiranyl; —OR′; and —NR′R″, wherein R′ and R″ areindependently selected from hydrogen, haloalkyl (such as haloC₁₋₆alkyl),alkyl (such as C₁₋₁₂alkyl, further such as C₁₋₆alkyl), and arylalkyl(such as phenylC₁₋₆alkyl, further such as phenylmethyl).

In some embodiments, R⁵ in Formula (III) is selected from hydrogen,alkyl, cycloalkyl, aryl, —COR⁹, and —COOR⁹, wherein each of the alkyl,cycloalkyl, and aryl is independently optionally substituted with atleast one substituent R¹², and R⁹ is alkyl or cycloalkyl optionallysubstituted with at least one substituent R¹², and R¹² is defined as forFormula (III). In some embodiments, R⁵ in Formula (III) is selected fromhydrogen, alkyl, cycloalkyl, aryl, —COR⁹, and —COOR⁹, wherein each ofthe alkyl, cycloalkyl, or aryl is independently optionally substitutedwith at least one substituent R¹², and R⁹ is alkyl or cycloalkyloptionally substituted with at least one substituent R¹², and R¹² isselected from NR′R″, aryl, and NR′CO₂R″, wherein R′ and R″ areindependently selected from hydrogen, haoloalkyl and alkyl. In somefurther embodiments, R⁵ in Formula (III) is selected from hydrogen;alkyl (such as C₁₋₁₂alkyl, further such as C₁₋₆alkyl) optionallysubstituted with at least one substituent selected from NR′R″ and aryl(such as phenyl); cycloalkyl (such as C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl);aryl (such as phenyl) optionally substituted with NR′R″; and —COR⁹,wherein R⁹ is cycloalkyl (such as C₃, C₄, C₅, C₆, C₇, C₈cycloalkyl), oralkyl (such as C₁₋₁₂alkyl, further such as C₁₋₆alkyl), each of thecycloalkyl and alkyl is optionally substituted with at least onesubstituent selected from NR′R″, aryl (such as phenyl), and —NR′CO₂R″,wherein R′ and R″ are independently selected from hydrogen, haloalkyl(such as haloC₁₋₆alkyl), and alkyl (such as C₁₋₆alkyl). In some furtherembodiments, R⁵ in Formula (III) is selected from hydrogen; C₁₋₆alkyl(such as methyl, ethyl, propyl, isopropyl, butyl, or 3,3-dimethylbutyl)optionally substituted with NR′R″; cyclohexyl; phenyl optionallysubstituted with NR′R″; and —COR⁹, wherein R⁹ is cyclopropyl, orC₁₋₆alkyl (such as methyl, ethyl, propyl, isopropyl, or butyl), each ofthe cycclopropyl and C₁₋₆alkyl is optionally substituted with at leastone substituent selected from NR′R″, aryl (such as phenyl), and—NR′CO₂R″, wherein R′ and R″ are independently selected from hydrogenand C₁₋₆alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, ortert-butyl).

In some embodiments, R⁴ and R⁵ in Formula (III), together with theatom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7- or8-membered saturated, partially or fully unsaturated ring having 0, 1 or2 additional heteroatoms independently selected from —NR¹³—, —O—, —S—,—SO— or —SO₂—, and said ring is optionally substituted with at least onesubstituent R¹² as defined for Formula (III). In some furtherembodiments, R⁴ and R⁵ in Formula (III), together with the atom(s) towhich they are attached, form a 5-membered saturated ring having onenitrogen heteroatom.

In some embodiments, R³ and R⁴ in Formula (III), which may be the sameor different, are each independently selected from hydrogen, alkyl (suchas C₁₋₁₂alkyl, further such as C₁₋₆alkyl), and OH.

Also provided herein is at least one compound selected from thefollowing compounds, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof,

Also provided herein is a method of inhibiting the activity of PARP. Themethod comprises contacting the PARP with at least one compound, atleast one stereoisomer thereof, and/or at least one pharmaceuticallyacceptable salt thereof described herein in an amount effective toinhibit the activity of the PARP.

Also provided herein is a method of treating at least one diseaseresponsive to inhibition of PARP comprising administering to a subject,such as a mammal or human, in recognized need of such treating for theat least one disease an amount of at least one compound, at least onestereoisomer thereof, and/or at least one pharmaceutically acceptablesalt thereof described herein.

The at least one disease can be selected from, for example, ovariancancer, carcinomas of the breast, colon cancer, leukemia, glioblastomas,lymphomas, melanomas, cervical carcinomas and other cytotoxic cancers.

The at least one compound, at least one stereoisomer thereof, and/or atleast one pharmaceutically acceptable salt thereof disclosed herein maybe employed alone or in combination with radiation and chemotherapy by,for example, increasing apoptosis of cancer cells, limiting tumorgrowth, decreasing metastasis, and prolonging the survival oftumor-bearing mammals.

In some embodiments, the at least one compound, at least onestereoisomer thereof, and/or at least one pharmaceutically acceptablesalt thereof disclosed herein can be used in combination with at leastone additional therapeutic agent, such as at least one additionalchemotherapeutic agent.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Chemotherapeuticagents include compounds used in “targeted therapy” and conventionalchemotherapy. Suitable chemotherapeutic agents can be, for example,selected from: agents that induce apoptosis; polynucleotides (e.g.,ribozymes); polypeptides (e.g., enzymes); drugs; biological mimetics;alkaloids; alkylating agents; antitumor antibiotics; antimetabolites;hormones; platinum compounds; monoclonal antibodies conjugated withanticancer drugs, toxins, and/or radionuclides; biological responsemodifiers (e.g., interferons, such as IFN-a and interleukins, such asIL-2); adoptive immunotherapy agents; hematopoietic growth factors;agents that induce tumor cell differentiation (e.g., all-trans-retinoicacid); gene therapy reagents; antisense therapy reagents andnucleotides; tumor vaccines; and inhibitors of angiogenesis.

Examples of chemotherapeutic agents include Erlotinib (TARCEVA®,Genentech/OSI Pharm.); Bortezomib (VELCADE®, Millennium Pharm.);Fulvestrant (FASLODEX®, AstraZeneca); Sunitinib (SUTENT®, Pfizer);Letrozole (FEMARA®, Novartis); Imatinib mesylate (GLEEVEC®, Novartis);PTK787/ZK 222584 (Novartis); Oxaliplatin (Eloxatin®, Sanofi); 5-FU(5-fluorouracil); Leucovorin; Rapamycin (Sirolimus, RAPAMUNE®, Wyeth);Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline); Lonafarnib (SCH66336); Sorafenib (NEXAVAR®, Bayer); Irinotecan (CAMPTOSAR®, Pfizer) andGefitinib (IRESSA®, AstraZeneca); AG1478, AG1571 (SU 5271, Sugen);alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopa, and uredopa; ethylenimines andmethylamelamines such as altretamine, triethylenemelamine,triethylenephosphoramide, triethylenethiophosphoramide andtrimethylomelamine; acetogenins (such as bullatacin and bullatacinone);a camptothecin (such as the synthetic analog topotecan); bryostatin;callystatin; CC-1065 and its adozelesin, carzelesin and bizelesinsynthetic analogs; cryptophycins (such as cryptophycin 1 andcryptophycin 8); dolastatin; duocarmycin and the synthetic analogsthereof, such as KW-2189 and CB1-TM1; eleutherobin; pancratistatin; asarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,chlomaphazine, chlorophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, and ranimnustine; antibiotics such as the enediyneantibiotics (e.g., calicheamicin, such as calicheamicin gammall andcalicheamicin omegall (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186);dynemicin, such as dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores, aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminol evulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (such as T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®(Cremophor-free), albumin-engineered nanoparticle Formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France);chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate;daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11;topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);retinoids such as retinoic acid; and pharmaceutically acceptable salts,acids and derivatives of any of the above.

The “chemotherapeutic agent” can also be selected, for example, from:(i) anti-hormonal agents that act to regulate or inhibit hormone actionon tumors such as anti-estrogens and selective estrogen receptormodulators (SERMs), including, for example, tamoxifen (includingNOLVADEX®; tamoxifen citrate), raloxifene, droloxifene,4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, andFARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibitthe enzyme aromatase, which regulates estrogen production in the adrenalglands, such as, for example, 4(5)-imidazoles, aminoglutethimide,MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer),formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole;Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii)anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide,and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleosidecytosine analog); (iv) protein kinase inhibitors; (v) lipid kinaseinhibitors; (vi) antisense oligonucleotides, such as those which inhibitexpression of genes in signaling pathways implicated in aberrant cellproliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii)ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2expression inhibitors; (viii) vaccines such as gene therapy vaccines,for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; atopoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; (ix)anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and(x) pharmaceutically acceptable salts, acids and derivatives of any ofthe above.

The “chemotherapeutic agent” can also be selected, for example, fromtherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), tositumomab (Bexxar, Corixia), and the antibody drugconjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanized monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination with the at least one compound,at least one stereoisomer thereof, and/or at least one pharmaceuticallyacceptable salt thereof disclosed herein may, for example, be selectedfrom: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab,bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab,certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab,efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumabozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab,matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab,nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab,palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab,pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab,resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab,sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab,tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin,tucusituzumab, umavizumab, urtoxazumab, and visilizumab.

Also provided herein is a composition comprising at least one compound,at least one stereoisomer thereof, and/or at least one pharmaceuticallyacceptable salt thereof disclosed herein, and at least onepharmaceutically acceptable carrier.

The composition comprising at least one compound, at least onestereoisomer thereof, and/or at least one pharmaceutically acceptablesalt disclosed herein can be administered in various known manners, suchas orally, topically, rectally, parenterally, by inhalation spray, orvia an implanted reservoir, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The term “parenteral” as used herein includes subcutaneous,intracutaneous, intravenous, intramuscular, intraarticular,intraarterial, intrasynovial, intrasternal, intrathecal, intralesionaland intracranial injection or infusion techniques. The compositionsdisclosed herein may be conveniently presented in unit dosage form andprepared by any of the methods well known in the art.

The at least one compound, at least one stereoisomer thereof, and/or atleast one pharmaceutically acceptable salt thereof disclosed herein canbe administered orally in solid dosage forms, such as capsules, tablets,troches, dragées, granules and powders, or in liquid dosage forms, suchas elixirs, syrups, emulsions, dispersions, and suspensions. The atleast one compound, at least one stereoisomer thereof, and/or at leastone pharmaceutically acceptable salt thereof disclosed herein can alsobe administered parenterally, in sterile liquid dosage forms, such asdispersions, suspensions or solutions. Other dosages forms that can alsobe used to administer the at least one compound, at least onestereoisomer thereof, and/or at least one pharmaceutically acceptablesalt thereof disclosed herein as an ointment, cream, drops, transdermalpatch or powder for topical administration, as an ophthalmic solution orsuspension formation, i.e., eye drops, for ocular administration, as anaerosol spray or powder composition for inhalation or intranasaladministration, or as a cream, ointment, spray or suppository for rectalor vaginal administration.

Gelatin capsules containing the at least one compound, at least onestereoisomer thereof, and/or the at least one pharmaceuticallyacceptable salt thereof disclosed herein and powdered carriers, such aslactose, starch, cellulose derivatives, magnesium stearate, stearicacid, and the like, can also be used. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of time. Compressed tablets can be sugar coatedor film coated to mask any unpleasant taste and protect the tablet fromthe atmosphere, or enteric coated for selective disintegration in thegastrointestinal tract.

Liquid dosage forms for oral administration can further comprise atleast one agent selected from coloring and flavoring agents to increasepatient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene gycols can be examples of suitable carriers for parenteralsolutions. Solutions for parenteral administration may comprise a watersoluble salt of the at least one compound describe herein, at least onesuitable stabilizing agent, and if necessary, at least one buffersubstance. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, can be examples ofsuitable stabilizing agents. Citric acid and its salts and sodium EDTAcan also be used as examples of suitable stabilizing agents. Inaddition, parenteral solutions can further comprise at least onepreservative, selected, for example, from benzalkonium chloride, methyl-and propylparaben, and chlorobutanol.

A pharmaceutically acceptable carrier is, for example, selected fromcarriers that are compatible with active ingredients of the composition(and in some embodiments, capable of stabilizing the active ingredients)and not deleterious to the subject to be treated. For example,solubilizing agents, such as cyclodextrins (which can form specific,more soluble complexes with the at least one compound and/or at leastone pharmaceutically acceptable salt disclosed herein), can be utilizedas pharmaceutical excipients for delivery of the active ingredients.Examples of other carriers include colloidal silicon dioxide, magnesiumstearate, cellulose, sodium lauryl sulfate, and pigments such as D&CYellow #10. Suitable pharmaceutically acceptable carriers are describedin Remington's Pharmaceutical Sciences, A. Osol, a standard referencetext in the art.

Suitable in vitro assays can be used to preliminarily evaluate theefficacy of the at least one compound, at least one stereoisomerthereof, and/or at least one pharmaceutically acceptable salt thereofdisclosed herein, in inhibiting the activity of PARP. The at least onecompound, at least one stereoisomer thereof, and/or at least onepharmaceutically acceptable salt thereof disclosed herein can further beexamined for efficacy in treating cancer by in vivo assays. For example,the at least one compound, at least one stereoisomer thereof, and/or theat least one pharmaceutically acceptable salts thereof disclosed hereincan be administered to an animal (e.g., a mouse model) having cancer andits therapeutic effects can be accessed. Positive results in one or moreof such tests are sufficient to increase the scientific storehouse ofknowledge and hence sufficient to demonstrate practical utility of theat least one compound, at least one stereoisomer thereof, and/or atleast one pharmaceutically acceptable salt thereof tested. Based on theresults, an appropriate dosage range and administration route foranimals, such as humans, can also be determined.

For administration by inhalation, the at least one compound, at leastone stereoisomer thereof, and at least one pharmaceutically acceptablesalt thereof disclosed herein may be conveniently delivered in the formof an aerosol spray presentation from pressurized packs or nebulisers.The at least one compound, at least one stereoisomer thereof, and/or atleast one pharmaceutically acceptable salt thereof disclosed herein mayalso be delivered as powders, which may be formulated and the powdercomposition may be inhaled with the aid of an insufflation powderinhaler device. One exemplary delivery system for inhalation can be ametered dose inhalation (MDI) aerosol, which may be formulated as asuspension or solution of at least one compound, at least onestereoisomer thereof, and/or at least one pharmaceutically acceptablesalt thereof disclosed herein in at least one suitable propellant,selected, for example, from fluorocarbons and hydrocarbons.

For ocular administration, an ophthalmic preparation may be formulatedwith an appropriate weight percentage of a solution or suspension of theat least one compound, at least one stereoisomer thereof, and/or atleast one pharmaceutically acceptable salt thereof disclosed herein inan appropriate ophthalmic vehicle, such that the at least one compound,stereoisomers thereof, and pharmaceutically acceptable salts thereofdisclosed herein is maintained in contact with the ocular surface for asufficient time period to allow the compound to penetrate the cornealand internal regions of the eye.

Useful pharmaceutical dosage-forms for administration of the at leastone compound, at least one stereoisomer thereof, and/or at least onepharmaceutically acceptable salt thereof disclosed herein include, butare not limited to, hard and soft gelatin capsules, tablets, parenteralinjectables, and oral suspensions.

The dosage administered will be dependent on factors, such as the age,health and weight of the recipient, the extent of disease, type ofconcurrent treatment, if any, frequency of treatment, and the nature ofthe effect desired. In general, a daily dosage of the active ingredientcan vary, for example, from 0.1 to 2000 milligrams per day. For example,10-500 milligrams once or multiple times per day may be effective toobtain desired results.

In some embodiments, a large number of unit capsules can be prepared byfilling standard two-piece hard gelatin capsules each with, for example,100 milligrams of the at least one compound, stereoisomers thereof, andpharmaceutically acceptable salts thereof disclosed herein in powder,150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligramsmagnesium stearate.

In some embodiments, a mixture of the at least one compound, at leastone stereoisomer thereof, and/or at least one pharmaceuticallyacceptable salt thereof disclosed herein in a digestible oil such assoybean oil, cottonseed oil or olive oil can be prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules are washed and dried.

In some embodiments, a large number of tablets can be prepared byconventional procedures so that the dosage unit comprises, for example,100 milligrams of the at least one compound, at least one stereoisomerthereof, and/or at least one pharmaceutically acceptable salt thereofdisclosed herein, 0.2 milligrams of colloidal silicon dioxide, 5milligrams of magnesium stearate, 275 milligrams of microcrystallinecellulose, 11 milligrams of starch and 98.8 milligrams of lactose.Appropriate coatings may be applied to increase palatability or delayabsorption.

In some embodiments, a parenteral composition suitable foradministration by injection can be prepared by stirring 1.5% by weightof the at least one compound, at least one stereoisomer thereof, and/orat least one pharmaceutically acceptable salt thereof disclosed hereinin 10% by volume propylene glycol. The solution is made to the expectedvolume with water for injection and sterilized.

In some embodiment, an aqueous suspension can be prepared for oraladministration. For example, each 5 milliliters of an aqueous suspensioncomprising 100 milligrams of finely divided at least one compound, atleast one stereoisomer thereof, and/or at least one pharmaceuticallyacceptable salt thereof disclosed herein, 100 milligrams of sodiumcarboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams ofsorbitol solution, U.S.P., and 0.025 milliliters of vanillin can beused.

The same dosage forms can generally be used when the at least onecompound, at least one stereoisomer thereof, and/or at least onepharmaceutically acceptable salt thereof disclosed herein areadministered stepwise or in conjunction with at least one othertherapeutic agent. When drugs are administered in physical combination,the dosage form and administration route should be selected depending onthe compatibility of the combined drugs. Thus the term coadministrationis understood to include the administration of at least two agentsconcomitantly or sequentially, or alternatively as a fixed dosecombination of the at least two active components.

The at least one compound, stereoisomers thereof, and pharmaceuticallyacceptable salts thereof disclosed herein can be administered as thesole active ingredient or in combination with at least one second activeingredient, selected, for example, from other active ingredients knownto be useful for treating cancers in a patient.

General Synthetic Schemes

The compounds disclosed herein, and/or the pharmaceutically acceptablesalts thereof, can be synthesized from commercially available startingmaterials taken together with the disclosure herein. The followingschemes illustrate methods for preparation of some of the compoundsdisclosed herein.

In this scheme, an alkyl 3-amino-2-Lv-benzoate (Lv=leaving group, suchas Br, I, OTf) of formula 1 is reacted with a cyclic 1,3-carbonyls offormula 2 to provide an enaminone of formula 3. The subsequentcyclization under a catalyst, such as palladium, gives an alkyloxocarbazole carboxylate of formula 4 which is subsequently cyclizedwith hydrazine to provide the diazepinocarbazolone derivative of Formula(I), (II) or (III).

The first step of this scheme can be conducted in Dean-Stark apparatusin a solvent such as tolueneunder reflux. The resulting enaminone offormula 3 is purified on a flash column.

The second step of this sequence can be conducted using apalladium/phosphine catalyst at elevated temperature in acetonitrile orDMF and this intramolecular Heck reaction (Bozell, J. J., Hegedus, L. S.J. Org. Chem. 1981, 46, 2561; Maruyama, J., Yamashida, H., Watanabe, T.,Arai, S., Nishida, A. Tetrahedron 2009, 65, 1327, incorporated herein byreference) can be usually completed in about 5-24 hours. The alkyloxocarbazole carboxylate of formula 4 can be then isolated usingstandard conditions for the workup and it may be purified by eitherchromatographic methods or by recrystallization.

The third step of the synthesis of the novel compounds of Formula (I) isan intermolecular cyclization reaction of a compound of formula 4 toprovide the diazepinocarbazolone derivative of Formula (I), (II) or(III) as shown Scheme 1. This cyclization reaction can be typicallyconducted using 1-2 equivalents of hydrous hydrazine and the appropriatealcohol as solvent. The cyclization reaction can be typically conductedat a temperature ranging from 50° C. to the refluxing temperature of thealcohol and it can be completed, for instance, in 0.25 to 4 hours.

The synthesis of some of the compounds of Formula (III) can be describedin Scheme 2. The compound of formula a which is also a compound ofFormula (III), can be prepared according to Scheme 1.

The compound of formula a is de-protected to give a compound of formulab (which is also a compound of Formula (III)). Further reaction of thecompound of formula b with electrophile such as alkyl halide, arylhalides, acids, acyl chlorides, sulfonyl chlorides, aldehyde, ketone,etc, gives some of the compounds of Formula (III) under thecorresponding alkylation, coupling, or reductive alkylation conditions.

EXAMPLES

The examples below are intended to be purely exemplary and should not beconsidered to be limiting in any way. Efforts have been made to ensureaccuracy with respect to numbers used (for example, amounts,temperature, etc.), but some experimental errors and deviations shouldbe accounted for. Unless indicated otherwise, temperature is in degreesCentigrade. Reagents were purchased from commercial suppliers such asSigma-Aldrich, Alfa Aesar, or TCI, and were used without furtherpurification unless indicated otherwise.

Unless indicated otherwise, the reactions set forth below were performedunder a positive pressure of nitrogen or argon or with a drying tube inanhydrous solvents; the reaction flasks were fitted with rubber septafor the introduction of substrates and reagents via syringe; andglassware was oven dried and/or heat dried.

Unless otherwise indicated, column chromatography purification wasconducted on a Biotage system (Manufacturer: Dyax Corporation) having asilica gel column or on a silica SepPak cartridge (Waters), or wasconducted on a Teledyne Isco Combiflash purification system usingprepacked silica gel cartridges.

¹H NMR spectra were recorded on a Varian instrument operating at 400MHz. ¹HNMR spectra were obtained using CDCl₃, CD₂Cl₂, CD₃OD, D₂O,d₆-DMSO, d₆-acetone or (CD₃)₂CO as solvent and tetramethylsilane (0.00ppm) or residual solvent (CDCl₃: 7.25 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79ppm; d₆-DMSO: 2.50 ppm; d₆-acetone: 2.05; (CD3)2CO: 2.05) as thereference standard. When peak multiplicities are reported, the followingabbreviations are used: s (singlet), d (doublet), t (triplet), q(quartet), qn (quintuplet), sx (sextuplet), m (multiplet), br(broadened), dd (doublet of doublets), dt (doublet of triplets).Coupling constants, when given, are reported in Hertz (Hz). All compoundnames except the reagents were generated by Chemdraw version 12.0.

In the following examples, the abbreviations below are used:

-   -   AcOH Acetic acid    -   Aq Aqueous    -   Brine Saturated aqueous sodium chloride solution    -   CH₂Cl₂ Dichloromethane    -   DMF N,N-Dimethylformamide    -   Dppf 1,1″-bis(diphenylphosphino)ferrocene    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DIEA N,N-diisopropylethylamine    -   DMAP 4-N,N-dimethylaminopyridine    -   DMF N,N-dimethylformamide    -   DMSO Dimethyl sulfoxide    -   EtOAc Ethyl acetate    -   EtOH Ethanol    -   Et₂O or ether Diethyl ether    -   G grams    -   h or hr hour    -   HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium        hexafluorophosphate Methanaminium    -   HCl Hydrochloric acid    -   HPLC High-performance liquid chromatography    -   IPA 2-propanol    -   i-PrOH Isopropyl alcohol    -   Mg milligrams    -   mL milliliters    -   Mmol millimole    -   MeCN Acetonitrile    -   MeOH Methanol    -   Min minutes    -   ms or MS Mass spectrum    -   Na₂SO₄ Sodium sulfate    -   Rt Retention time    -   Rt or rt Room temperature    -   TFA Trifluoroacetic acid    -   THF tetrahydrofuran    -   TLC thin layer chromatography    -   μL microliters

In the following examples, the abbreviations below are used:

Example 1 Synthesis of Compounds 1-19 Compound 1:2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

Step 1: Methyl 2-bromo-3-((3-oxocyclohex-1-en-1-yl)amino)benzoate

Methyl 3-amino-2-bromobenzoate (2.39 g, 10.0 mmol) andcyclohexane-1,3-dione (1.12 g, 10.0 mmol) were dissolved in 10 mL ofacetic acid at 25° C., under nitrogen. The mixture was stirred at 80° C.for 8 hours. The resultant solid was purified by chromatography columnon silica gel (elution with hexane/ethyl acetate) to afford 2.46 g (76%)of methyl 2-bromo-3-((3-oxocyclohex-1-en-1-yl)amino)benzoate as a tanfoam. ¹H NMR (CDCl₃-d1) δ 7.53-7.55 (m, 2H), 7.37 (dd, 1H, J=7.2, 8.4Hz), 6.34 (br s, 1H), 5.57 (s, 1H), 3.95 (s, 3H), 2.56-2.59 (m, 2H),2.40-2.42 (m, 2H), and 2.08-2.11 (m, 2H). MS (ESI) m/e [M+1]⁺ 324.0.

Step 2: Methyl 4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate

A mixture of methyl 2-bromo-3-(3-oxocyclohex-1-enylamino)benzoate (0.97g, 3.0 mmol), palladium acetate (0.14 g, 0.6 mmol), tri-o-tolylphosphine(0.73 g, 2.4 mmol), and triethylamine (0.38 g, 3.6 mmol) in acetonitrile(10 mL) was heated in a sealed tubule flushed with nitrogen at 100° C.for 20 h. The cooled reaction mixture was diluted with DCM (3×50 mL) andwater (10 mL). The organic layer was separated, washed with water, dried(Na₂SO₄), and concentrated. The remaining residue was chromatographed onsilica gel, eluted with gradient 0-100% EtOAc in hexane to afford thetitle compound (0.61 g, 84%). ¹H NMR (CDCl₃-d1) δ 9.47 (s, 1H),7.36-7.40 (m, 2H), 7.22 (t, 1H, J=7.8 Hz), 2.90-2.92 (m, 2H), 2.51-2.54(m, 2H), and 2.14-2.16 (m, 2H). MS (ESI) m/e [M+1]⁺ 244.0.

Step 3:2,3,5,10-Tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

A solution of compound methyl4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate (73 mg, 0.3 mmol),acetic acid (0.15 mL, 2.6 mmol), and hydrazine hydrate (0.86 mL, 1.5mmol) in methanol (4 mL) was heated at reflux. After 8 h, the solid wascollected by hot filtration and washed with water, EtOAc, anddichloromethane, to give the target compound (42 mg, 62%). ¹H NMR(DMSO-d₆) δ 11.70 (s, 1H), 9.79 (s, 1H), 7.36-7.38 (m, 2H), 7.05 (t, 1H,J=7.8 Hz), 2.77-2.79 (m, 2H), 2.35-2.37 (m, 2H), and 1.92-1.93 (m, 2H).MS (ESI) m/e [M+1]⁺ 226.0.

The following examples, Compounds 2 through 19, were prepared accordingto the procedure for Compound 1 by using the corresponding substitutedor unsubstituted methyl 3-amino-2-bromobenzoate and cyclic 1,3-dioneunder appropriate conditions that could be recognized by one skilled inthe art.

Compound ¹H NMR data LC/MS No. Name m/z (M + 1) Structure 25,6,7,8-tetrahydro- 4H-4,9,10- triazaindeno[2,1,7- kla]heptalen-11(10H)-one (DMSO-d₆) δ 11.74 (s, 1H), 9.79 (s, 1H), 7.46 (d, 1H, J =7.8 Hz), 7.38 (d, 1H, J = 7.8 Hz), 7.07(t, 1H, J = 7.8 Hz), 2.98-3.01(m, 2H), 2.59-2.61 (m, 2H), 1.89-1.94 (m, 2H), and 1.70-1.84 (m, 2H).MS(ESI) m/e [M + 1]⁺ 240.0.

3 2-methyl-2,3,5,10- tetrahydro- [1,2]diazepino[3,4, 5,6-def]carbazol-6(1H)-one (DMSO-d₆) δ 11.70 (s, 1H), 9.81 (s, 1H), 7.40-7.42 (m, 2H),7.08 (t, 1H, J = 7.8 Hz), 2.88-2.92 (m, 1H), 2.40-2.42 (m, 2H),2.14-2.19 (m, 2H), and 1.10 (d, 3H, J = 6.0 Hz). MS (ESI) m/e [M + 1]⁺240.0.

.4 3,3-dimethyl- 2,3,5,10-tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.70 (s, 1H), 9.89 (s, 1H),7.39-7.41 (m, 2H), 7.08 (t, 1H, J = 7.8 Hz), 2.82-2.84 (m, 1H),1.79-1.81 (m, 2H), and 1.16 (s, 6H). MS (ESI) m/e [M + 1]⁺ 254.0.

5 2-phenyl-2,3,5,10- tetrahydro- [1,2]diazepino[3,4, 5,6-def]carbazol-6(1H)-one (DMSO-d₆) δ 11.74 (s, 1H), 9.84 (s, 1H), 7.21-7.42 (m, 7H),7.07 (t, 1H, J = 7.8 Hz), 3.24-3.28 (m, 2H), 3.01-3.08 (m, 1H), and2.70-2.75 (m, 2H). MS (ESI) m/e [M + 1]⁺ 302.0.

6 2-isopropyl- 2,3,5,10-tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.70 (s, 1H), 9.82 (s, 1H),7.42 (m, 2H), 7.09 (t, 1H, J = 7.8 Hz), 2.84- 2.87 (m, 1H), 2.59-2.64(m, 1H), 2.42- 2.49 (m, 1H), 2.20-2.24 (m, 1H), 1.82- 1.85 (m, 1H),1.69-1.72 (m, 1H), and 0.98 (6H, d, J = 7.2 Hz). MS (ESI) m/e [M + 1]⁺268.

7 8-fluoro-2,3,5,10- tetrahydro- [1,2]diazepino[3,4, 5,6-def]carbazol-6(1H)-one (DMSO-d₆) δ 11.83 (s, 1H), 10.03 (s, 1H), 7.23 (dd, 1H, J =10.8, 1.8 Hz), 7.12 (dd, 1H, J = 11.4, 1.8 Hz), 2.76-2.78 (m, 2H),2.35-2.37 (m, 2H), 1.91-1.93 (m, 2H). MS (ESI) m/e [M + 1]⁺ 244.

8 2-fluoro-5,6,7,8- tetrahydro-4H- 4,9,10- triazaindeno[2,1,7-kla]heptalen- 11(10H)-one (DMSO-d₆) δ 11.84 (s, 1H), 10.02 (s, 1H),7.17-7.22 (m, 2H), 2.95-2.97 (m, 2H), 2.56-2.58 (m, 2H), 1.77-1.88 (m,4H). MS (ESI) m/e [M + 1]⁺ 258.

9 8-fluoro-2,2- dimethyl-2,3,5,10- tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.84 (s, 1H), 10.08 (s, 1H),7.29 (dd, 1H, J = 10.8, 1.8 Hz), 7.18 (dd, 1H, J = 11.4, 1.8 Hz),2.63-2.67 (m, 2H), 2.25-2.26 (m, 2H), 1.06 (s, 6H). MS (ESI) m/e [M +1]⁺ 272.

10 8-fluoro-2-phenyl- 2,3,5,10-tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.92 (s, 1H), 10.11 (s, 1H),7.18-7.40 (m, 7H), 3.31-3.32 (m, 1H), 3.05-3.07 (m, 2H), 2.74-2.77 (m,1H), 2.55-2.56 (m, 1H). MS (ESI) m/e [M + 1]⁺ 320.

11 8-fluoro-2- isopropyl-2,3,5,10- tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.82 (s, 1H), 10.04 (s, 1H),7.15-7.29 (m, 2H), 2.82-2.85 (m, 1H), 2.57-2.61 (m, 1H), 2.41-2.44 (m,1H), 2.19-2.44 (m, 1H), 1.82-1.83 (m, 1H), 1.69-1.71 (m, 1H), 0.97 (d,6H, J = 9.0 Hz). MS (ESI) m/e [M + 1]⁺ 286.

12 2-(4- (dimethylamino) phenyl)-8-fluoro- 2,3,5,10-tetrahydro-[1,2]diazepino[3,4, 5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.89 (s,1H), 10.09 (s, 1H), 7.29 (dd, 1H, J = 9.0, 1.8 Hz), 7.17-7.19 (m, 3H),6.69 (d, 2H, J = 8.4 Hz), 3.19-3.21 (m, 1H), 2.98-3.00 (m, 2H),2.86 (s,6H), 2.66-2.69 (m, 1H),2.48-2.51 (m, 1H). MS (ESI) m/e [M + 1]⁺ 363.

13 2-(4- (dimethylamino) phenyl)-2,3,5,10- tetrahydro-[1,2]diazepino[3,4, 5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.76 (s,1H), 9.84 (s, 1H), 7.42 (d, 2H, J = 7.8 Hz), 7.03-7.17 (m, 3H), 6.69 (d,2H, J = 7.8 Hz), 3.16-3.17 (m, 1H), 2.99-3.01 (m, 2H), 2.70 (s, 6H),2.65-2.68 (m, 1H), 2.48-2.50 (m, 1H). MS (ESI) m/e [M + 1]⁺ 345.

14 8-fluoro-3,3- dimethyl-2,3,5,10- tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.7 (s, 1H), 10.1 (s, 1H), 7.26(dd, 1H, J = 9.6, 2.4 Hz), 7.16 (dd, 1H, J = 10.2, 2.4 Hz), 2.81-2.83(m, 2H), 1.74-1.81 (m, 2H), and 1.16 (s, 6H). MS (ESI) m/e [M + 1]⁺ 272.

15 2,2-dimethyl- 2,3,5,10-tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.69 (s, 1H), 9.84 (s, 1H),7.42 (d, 2H, J = 7.8 Hz), 7.09 (t, 1H, J = 7.8 Hz), 2.67 (s, 2H), 2.23(s, 2H), 1.05 (s, 6H). MS (ESI) m/e [M + 1]⁺ 254.

16 7-fluoro-2,2- dimethyl-2,3,5,10- tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.75 (s, 1H), 9.60 (s, 1H),7.41 (dd, 1H, J = 9.0, 3.0 Hz), 6.87 (dd, 1H, J = 12.0, 3.0 Hz), 2.65(s, 2H), 2.21 (s, 2H), 1.05 (s, 6H). MS (ESI) m/e [M + 1]⁺ 272.

17 9-fluoro-2,3,5,10- tetrahydro- [1,2]diazepino[3,4, 5,6-def]carbazol-6(1H)-one (DMSO-d₆) δ 12.26 (s, 1H), 9.93 (s, 1H), 7.43 (dd, 1H, J =8.4, 4.8 Hz), 6.96 (dd, 1H, J = 13.3, 8.4 Hz), 2.82-2.85 (m, 2H),2.41-2.43 (m, 2H), 1.97-1.99 (m, 2H). MS (ESI) m/e [M + 1]⁺ 244.

18 8-fluoro-2-methyl- 2,3,5,10-tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 12.1 (s, 1H), 10.0 (s, 1H), 7.26(dd, 1H, J = 9.6, 2.4 Hz), 7.16 (dd, 1H, J = 10.2, 2.4 Hz), 2.87-2.91(m, 1H), 2.40-2.43 (m, 2H), 2.15-2.19 (m, 2H), and 1.10 (d, 3H, J = 6.0Hz). MS (ESI) m/e [M + 1]⁺ 258.

19 8-fluoro-3,3- dimethyl-2,3,5,10- tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol- 6(1H)-one (DMSO-d₆) δ 11.7 (s, 1H), 10.1 (s, 1H), 7.26(dd, 1H, J = 9.6, 2.4 Hz), 7.16 (dd, 1H, J = 10.2, 2.4 Hz), 2.81-2.83(m, 2H), 1.74-1.81 (m, 2H), and 1.16 (s, 6H). MS (ESI) m/e [M + 1]⁺ 272.

Example 2 Synthesis of Compounds 20-21 Compound 20 Benzyl8-oxo-3,4,8,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluorene-2(1H)-carboxylate

Step 1: Benzyl3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate

Methyl 3-amino-2-bromobenzoate (0.25 g, 1.1 mmol) and benzyl3,5-dioxopiperidine-1-carboxylate (0.13 g, 0.55 mmol) were dissolved in10 mL of acetic acid at 25° C., under nitrogen. The mixture was stirredfor 8 hours at 70° C. The resultant solid was purified by chromatographycolumn on silica gel (elution with hexane/ethyl acetate) to afford 0.13g (51%) of benzyl3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylateas a tan foam. ¹H NMR (CDCl₃-d1) δ 7.53-7.58 (m, 3H), 7.42-7.48 (m, 5H),5.56 (s, 1H), 5.16 (s, 2H), 4.46 (s, 2H), 4.13 (s, 2H), 3.93 (s, 3H). MS(ESI) m/e [M+1]⁺ 459.0.

Step 2: 2-Benzyl 5-methyl4-oxo-3,4-dihydro-1H-pyrido[3,4-b]indole-2,5(9H)-dicarboxylate

A mixture of benzyl3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate(0.13 g, 0.28 mmol), palladium acetate (0.013 g, 0.06 mmol),tri-o-tolylphosphine (0.72 g, 0.19 mmol), and triethylamine (0.36 g,0.36 mmol) in acetonitrile (2 mL) was heated in a sealed tubule flushedwith nitrogen at 100° C. for 9 h. The cooled reaction mixture wasdiluted with DCM (3×50 mL) and water (10 mL). The organic layer wasseparated, washed with water, dried (Na₂SO₄), and concentrated. Theremaining residue was chromatographed on silica gel, eluted withgradient 0-100% EtOAc in hexane to give the title compound (0.076 g,72%). ¹H NMR (CDCl₃-d1) δ 9.62 (s, 1H), 7.24-7.50 (m, 8H), 5.18 (s, 2H),4.88 (s, 2H), 4.27 (s, 2H), 3.98 (s, 3H). MS (ESI) m/e [M+1]⁺ 379.0.

Step 3: Benzyl8-oxo-3,4,8,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluorene-2(1H)-carboxylate

A solution of compound 2-benzyl 5-methyl4-oxo-3,4-dihydro-1H-pyrido[3,4-b]indole-2,5(9H)-dicarboxylate (70 mg,0.18 mmol), acetic acid (0.15 mL, 2.6 mmol), and hydrazine hydrate (0.86mL, 1.5 mmol) in methanol (4 mL) was heated at reflux. After 8 h, thesolid was collected by hot filtration and washed with water, EtOAc, anddichloromethane, to give the target compound (61 mg, 94%). ¹HNMRDMSO-d₆) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.54 (d, 1H, J=8.4 Hz), 7.48(d, 1H, J=7.2 Hz), 7.38 (m, 4H), 7.32 (m, 1H), 7.18 (dd, 1H, J=8.4, 7.2Hz), 5.15 (s, 2H), 4.82 (m, 2H), 4.28 (m, 2H). MS (ESI) m/e [M+1]⁺ 361.

Compound 21

Benzyl6-fluoro-8-oxo-3,4,8,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluorene-2(1H)-carboxylate

Compound 21 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoateand benzyl 3,5-dioxopiperidine-1-carboxylate according to the proceduresfor Compound 20 under appropriate conditions recognized by one ofordinary skill in the art. ¹H NMR (DMSO-d₆) δ 11.9 (s, 1H), 10.3 (s,1H), 7.33-7.45 (m, 6H), 7.23 (dd, 1H, J=10.2, 1.8 Hz), 5.15 (s, 2H),4.79-4.83 (m, 2H), 4.28-4.30 (m, 2H). MS (ESI) m/e [M+1]⁺ 379.

Example 3 Synthesis of Compounds 22-25 Compound 22:10-Methyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

Step 1: Methyl9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate

To a solution of methyl4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate (0.27 g, 1 mmol) inTHF (5 ml) at 0° C. under N₂ was added potassium t-butoxide (0.12 g,1.05 mmol). The reaction mixture was stirred for 30 minutes followed bythe addition of methyl iodide (0.76 g, 5.0 mmol). After 3 hours, thereaction mixture was concentrated to a residue and partitioned betweenEtOAc (40 ml) and 1N HCl (5 ml). The layers were shaken and separated.The organic layer was washed with 1N HCl (2×80 ml) and brine (2×10 ml),dried over Na₂SO₄, filtered, and concentrated to give a solid (0.46 g).The solid was used in the next step without further purified. ¹H NMR(DMSO-d₆) δ 7.35-7.39 (m, 2H), 7.29 (t, 1H, J=7.2 Hz), 4.01 (s, 3H),3.72 (s, 3H), 2.93-2.95 (m, 2H), 2.54-2.56 (m, 2H), and 2.23-2.26 (m,2H). MS (ESI) m/e [M+1]⁺ 258.0

Step 2:10-Methyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

The desired product was prepared using a procedure similar to step 3 forCompound 1. ¹H NMR (DMSO-d₆) δ 9.88 (s, 1H), 7.55 (d, 1H, J=7.8 Hz),7.45 (d, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.8 Hz), 3.70 (s, 3H), 2.77-2.79(m, 2H), 2.35-2.37 (m, 2H), and 1.92-1.93 (m, 2H). MS (ESI) m/e [M+1]⁺240.0

Compound 23:2,2,10-trimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

Compound 23 was prepared from methyl2,2-dimethyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate andmethyl iodide according to the procedures for Compound 22 underappropriate conditions recognized by one of ordinary skill in the art.¹H NMR (DMSO-d₆) δ 9.86 (s, 1H), 7.42-7.53 (m, 2H), 7.12 (t, 1H, J=7.8Hz), 3.66 (s, 3H), 2.67 (s, 2H), 2.20 (s, 2H), and 1.04 (s, 6H). MS(ESI) m/e [M+1]⁺ 268.

Compound 24:10-Benzyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

Compound 24 was prepared from methyl2,2-dimethyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate andbenzyl chloride according to the procedures for Compound 22 underappropriate conditions recognized by one of ordinary skill in the art.¹H NMR (DMSO-d₆) δ 9.96 (s, 1H), 7.56 (d, 1H, J=8.4 Hz), 7.47 (d, 1H,J=7.8 Hz), 7.11-7.33 (m, 6H), 5.45 (s, 2H), 2.82-2.84 (m, 2H), 2.41-2.43(m, 2H), and 1.97-2.00 (m, 2H). MS (ESI) m/e [M+1]⁺ 316.

Compound 25:2,2,5,10-tetramethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

The desired product was prepared using a procedure similar to step 1 ofExample 22. Subsequently,2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one(0.02 g, 0.08 mmol) was reacted with NaH (2.4 mg, 0.1 mmol) and methyliodide (0.06 g, 0.4 mmol) in DMF (2 ml) to give the desired product (20mg, 95%) as yellow solid. ¹H NMR (DMSO-d₆) δ 7.51-7.55 (m, 2H), 7.16 (t,1H, J=7.8 Hz), 3.69 (s, 3H), 3.42 (s, 3H), 2.72 (s, 2H), 2.27 (s, 2H),and 1.09 (s, 6H). MS (ESI) m/e [M+1]⁺ 282.

Example 4 Synthesis of Compound 26 Compound 26:8-Fluoro-2,2-dimethyl-2,3-dihydro-[1,2]diazepino[3,4,5,6-def]carbazole-1,6(5H,10H)-dione

To a solution of carbamate8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one(0.5 g, 1.8 mmol) in anhydrous dioxane (25 mL) was added SeO₂ (0.32 g,2.7 mmol). The mixture was refluxed for 40 h and filtered throughCelite. The solid material was thoroughly washed with Et₂O. The filtratewas concentrated, and the residue was chromatographed to give product(200 mg, 38%) as a solid. ¹H NMR (DMSO-d₆) δ 12.70 (s, 1H), 10.90 (s,1H), 7.41 (dd, 1H, J=10.2, 1.8 Hz), 7.09 (dd, 1H, J=9.6, 1.8 Hz), 2.87(s, 2H), 1.23 (s, 6H). MS (ESI) m/e [M+1]⁺ 286.

Example 5 Synthesis of Compound 27 Compound 27:8-fluoro-1-hydroxy-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

To a solution of8-fluoro-2,2-dimethyl-2,3-dihydro-[1,2]diazepino[3,4,5,6-def]carbazole-1,6(5H,10H)-dione(50 mg, 0.18 mmol) in 10 mL of MeOH, was added NaBH₄ (0.18 mmol) at 0°C. The mixture was stirred for additional 30 min. The solution waspoured into ice water, and extracted with EtOAc (5 mL×3). The organiclayers were combined, washed with H₂O (5 mL×3) and brine (5 mL×3), driedover Na₂SO₄, and filtered. The filtrate was concentrated, and theresidue was chromatographed to give the crude product which was thenpurified on Pre-HPLC to give the product (5 mg) as a yellow solid. ¹HNMR (DMSO-d₆) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.23 (dd, 1H, J=9.2, 2.0Hz), 7.17 (dd, 1H, J=10.8, 2.4 Hz), 5.68 (d, 1H, J=6.0 Hz), 5.49 (d, 1H,J=6.0 Hz), 2.31 (s, 2H), 1.00 (s, 3H), and 0.88 (s, 3H). MS (ESI) m/e[M+1]⁺ 288.

Example 6 Synthesis of Compounds 28-39 Compound 28:10-(2-(dimethylamino)ethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

To a cooled solution (0° C.) of2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one(94 mg, 0.37 mmol) and DMF (10 mL) was added slowly K₂CO₃ (205 mg, 1.48mmol), then N,N-dimethylamino-2-chloroethane (53 mg, 0.37 mmol) wasadded. The resulting solution was stirred at 70° C. for 4 h. Thesolution was allowed to cool and water was added (10 mL). The mixturewas extracted with ethyl acetate (2×20 mL). The organic layers werecombined, dried over Na₂SO₄, and filtered. The filtrate wasconcentrated, and the residue was chromatographed to give the product(90 mg, 75%) as a yellow solid. ¹H NMR (DMSO-d₆) δ 9.91 (s, 1H), 7.58(d, 1H, J=7.8 Hz), 7.47 (d, 1H, J=7.8 Hz), 7.16 (t, 1H, J=7.8 Hz), 4.23(m, 2H), 2.74 (s, 2H), 2.51 (m, 2H), 2.25 (s, 2H), 2.18 (s, 6H), and1.07 (s, 6H). MS (ESI) m/e [M+1]⁺ 325.

Compounds 29-39 were synthesized according to the procedures forCompound 28 by using the corresponding starting material underappropriate conditions recognized by one of ordinary skill in the art.

Com- pound ¹H NMR data LC/MS No. Name m/z (M + 1) Structure 29 10-(2-(dibenzylamino)ethyl)- 2,2-dimethyl- 2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.87 (s,1H), 7.40 (d, 1H, J = 7.2 Hz), 7.31 (d, 1H, J = 7.6 Hz), 7.13-7.22 (m,10 H), 7.00 (dd, 1H, J = 7.2, 7.6 Hz), 4.15-4.18 (m, 2H), 3.61 (br s,4H), 2.56-2.59 (m, 2H), 2.24 (s, 2H), 2.11 (s, 2H), and 0.87 (s, 6H). MS(ESI) m/e [M + 1]⁺ 477.0.

30 2,2-dimethyl-10-(2- (pyrrolidin-1- yl)ethyl)-2,3,5,10- tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.91 (s,1H), 7.58 (d, 1H, J = 7.8 Hz), 7.47 (d, 1H, J = 7.2 Hz), 7.17 (dd, 1H, J= 7.2, 7.8 Hz), 4.23-4.26 (m, 2H), 2.69-2.74 (m 4H), 2.45 (br s, 4H),2.25 (br s, 2H), 1.64-1.65 (m, 4H), and 1.07 (s, 6H). MS (ESI) m/e [M +1]⁺ 351.0.

31 2,2-dimethyl-10-(2- (piperidin-1-yl)ethyl)- 2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.89 (s,1H), 7.57 (d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.17 (dd, 1H, J= 8.4, 7.8 Hz), 4.20-4.22 (m, 2H), 2.89 (br s, 2H), 2.50 (br s, 2H),2.35 (br s, 4H), 2.25 (br s, 2H), 1.35-1.46 (m, 6H), and 1.07 (s, 6H).MS (ESI) m/e [M + 1]⁺ 365.0.

32 2,2-dimethyl-10-(2- morpholinoethyl)- 2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.91(s, 1H),7.59 (d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.16 (dd, 1H, J =8.4, 7.8 Hz), 4.24-4.26 (m, 2H), 3.53-3.54 (m, 4H), 2.77 (br s, 2H),2.57-2.59 (m, 2H), 2.42 (br s, 4H), 2.25 (br s, 2H), and 1.08 (s, 6H).MS (ESI) m/e [M + 1]⁺ 367.0.

33 10-(2- (diethylamino)ethyl)- 2,2-dimethyl-2,3,5,10- tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.89 (s,1H), 7.56 (d, 1H, J = 7.8 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.15 (t, 1H, J= 7.8 Hz), 4.15- 4.17 (m, 2H), 2.76 (s, 2H), 2.62- 2.64 (m 2H),2.43-2.46 (m, 4H), 2.25 (s, 2H), 1.07 (s, 6H), and 0.81 (t, 6H, J = 7.2Hz). MS (ESI) m/e [M + 1]⁺ 353.0.

34 10-(2-(pyrrolidin-1- yl)ethyl)-2,3,5,10- tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.91 (s,1H), 7.57 (d, 1H, J = 7.8 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J= 7.8 Hz), 4.25- 4.27 (m, 2H), 2.87-2.89 (m 2H), 2.72 (br s, 2H),2.41-2.47 (m, 6H), 1.98-2.00 (m, 2H), and 1.66 (br s, 4H). MS (ESI) m/e[M + 1]⁺ 323.0.

35 10-(2-(piperidin-1- yl)ethyl)-2,3,5,10- tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.89 (s,1H), 7.57 (d, 1H, J = 7.8 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J= 7.8 Hz), 4.23- 4.25 (m, 2H), 2.89-2.91 (m 2H), 2.51-2.55 (m, 2H),2.36-2.43 (m, 6H), 1.98-2.00 (m, 2H), and 1.36- 1.45 (m, 6H). MS (ESI)m/e [M + 1]⁺ 337.0.

36 10-(2- morpholinoethyl)- 2,3,5,10-tetrahydro- [1,2]diazepino[3,4,5,6-def]carbazol-6(1H)- one (DMSO-d₆) δ 9.90 (s, 1H), 7.59 (d, 1H, J = 7.8Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 4.25- 4.27 (m,2H), 3.52-3.54 (m, 4H), 2.89-2.91(m, 2H), 2.58-2.60 (m, 2H), 2.41-2.43(m, 6H), and 1.99- 2.01 (m, 2H). MS (ESI) m/e [M + 1]⁺ 339.0.

37 10-(2- (dimethylamino)ethyl)- 2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.91 (s,1H), 7.58 (d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.16 (dd, 1H, J= 8.4, 7.8 Hz), 4.22-4.25 (m, 2H), 2.88-2.90 (m 2H), 2.41-2.47 (m, 4H),2.19 (s, 6H), and 1.92-2.00 (m, 2H). MS (ESI) m/e [M + 1]⁺ 297.0.

38 10-(2- (diethylamino)ethyl)- 2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.88 (s,1H), 7.56 (d, 1H, J = 7.2 Hz), 7.45 (d, 1H, J = 7.2 Hz), 7.15 (t, 1H, J= 7.2 Hz), 4.16- 4.18 (m, 2H), 2.89-2.91 (m 2H), 2.63-2.65 (m, 2H),2.40-2.45 (m, 6H), 1.98-2.00 (m, 2H), and 0.82 (t, 6H, J = 7.2 Hz). MS(ESI) m/e [M + 1]⁺ 325.0.

39 10-(2- (dibenzylamino)ethyl)- 2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6- def]carbazol-6(1H)- one (DMSO-d₆) δ 9.87 (s,1H), 7.40 (d, 1H, J = 7.6 Hz), 7.29 (d, 1H, J = 8.4 Hz), 7.06-7.19 (m,10 H), 6.98 (dd, 1H, J = 8.4, 7.6 Hz), 4.18-4.21 (m, 2H), 3.54-3.58 (d,4H, J = 8.8 Hz), 2.61-2.64 (m, 2H), 2.45-2.47 (m, 2H), 2.27-2.31 (m,2H), and 1.78- 1.81 (m, 2H). MS (ESI) m/e [M + 1]⁺ 449.0.

Example 7 Synthesis of Compound 40 Compound 40:10-(2-(dimethylamino)ethyl)-8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

Compound 40 was prepared from8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-oneand N,N-dimethylamino-2-chloroethane according to the procedures similarto those for Compound 28. ¹H NMR (DMSO-d₆) δ 10.1 (s, 1H), 7.56 (dd, 1H,J=9.6, 1.8 Hz), 7.21 (dd, 1H, J=10.2, 1.8 Hz), 4.22 (m, 2H), 2.74 (s,2H), 2.51 (m, 2H), 2.26 (s, 2H), 2.17 (s, 6H), and 1.06 (s, 6H). MS(ESI) m/e [M+1]⁺ 343.

Example 8 Synthesis of Compound 41 Compound 41:2,2-dimethyl-10-(oxiran-2-ylmethyl)-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

Compound 41 was prepared from2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-oneand 2-(chloromethyl)oxirane according to the procedures similar to thosefor Compound 28. ¹H NMR (DMSO-d₆) δ 9.96 (s, 1H), 7.65 (d, 1H, J=8.4Hz), 7.49 (d, 1H, J=7.8 Hz), 7.18 (dd, 1H, J=8.4, 7.8 Hz), 4.60-4.63 (m,1H), 4.21-4.24 (m, 1H), 3.27-3.29 (m, 1H), 2.76-2.77 (m, 1H), 2.75 (s,2H), 2.46-2.48 (m, 1H), 2.26 (s, 2H), and 0.92 (s, 6H). MS (ESI) m/e[M+1]⁺ 310.

Example 9 Synthesis of Compound 42 Compound 42:2,3,4,9-Tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

A mixture of Compound 20 (34 mg, 0.1 mmol) and palladium (10%) on carbon(10 mg) in 10 mL of methanol was stirred at RT under a balloon ofhydrogen for 5 h. The mixture was then filtered through a pad of celite.The catalyst cake was washed with methanol. The filtrate wasconcentrated. The resulting residue was purified by HPLC to give thetarget product as formic acid salt (white solid) (13 mg, 50%). ¹H NMR(DMSO-d₆) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.40-7.45 (m, 2H), 7.09 (t, 1H,J=8.0 Hz), 3.94 (s, 2H), 3.41 (s, 2H). MS (ESI) m/e [M+1]⁺ 227.

Example 10 Synthesis of Compound 43 Compound 43:6-Fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 43 was prepared from Compound 21 and palladium (10%) on carbonaccording to the procedures similar to those for Compound 42. ¹H NMR(DMSO-d₆) δ 11.8 (s, 1H), 10.04 (s, 1H), 7.29 (dd, 1H, J=10.0, 1.6 Hz),7.11 (dd, 1H, J=10.4, 1.6 Hz), 3.93 (s, 2H), 3.45 (s, 2H). MS (ESI) m/e[M+1]⁺ 245.

Example 11 Synthesis of Compound 44 Compound 44:2-Methyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Step 1: Methyl2-methyl-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate

Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate(0.04 g, 0.016 mmol) and NaCNBH₃ (2.4 mg, 0.04 mmol) were added to around bottomed flask, which were then dissolved in MeOH (2 mL), andtreated with 0.5 mL of a 27% solution of formaldehyde in water. Thismixture was stirred for 2 h, after which, 2N HCl (2 mL) was added,followed by stirring for 15 min. The mixture was taken to pH=11 byaddition of concentrated, aqueous NaOH and extracted with methylenechloride (3×10 mL). The combined organic layers were washed with brine,dried (Na₂SO₄), and concentrated. The crude product was used in the nextstep without further purification.

Step 2:2-Methyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 44 was prepared from Methyl2-methyl-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylateand hydrazine hydrate according to the procedure similar to that forCompound 1. ¹H NMR (DMSO-d₆) δ 11.7 (s, 1H), 9.87 (s, 1H), 7.43 (d, 1H,J=8.0 Hz), 7.39 (d, 1H, J=7.6 Hz), 7.14 (dd, 1H, J=8.0, 7.6 Hz), 3.70(s, 2H), 3.13 (s, 2H), and 2.39 (s, 3H). MS (ESI) m/e [M+1]⁺ 241.

Example 12 Synthesis of Compound 45 Compound 45:2-Isopropyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 45 was prepared from methyl4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate andacetone according to the procedures similar to those for Compound 44. ¹HNMR (DMSO-d₆) δ 11.7 (s, 1H), 9.83 (s, 1H), 7.43 (d, 1H, J=8.4 Hz), 7.38(d, 1H, J=7.6 Hz), 7.08 (dd, 1H, J=8.4, 7.6 Hz), 3.78 (s, 2H), 3.26 (s,2H), 2.93-2.96 (m, 1H), 1.04 (d, 6H, J=6.4 Hz). MS (ESI) m/e [M+1]⁺ 269.

Example 13 Synthesis of Compound 46 Compound 46:6-Fluoro-2-isopropyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 46 was prepared from methyl7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylateand acetone according to the procedures similar to those for Compound44. ¹H NMR (DMSO-d₆) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.35 (dd, 1H, J=2.4,9.6 Hz), 7.18 (dd, 1H, J=2.4, 10.2 Hz), 3.82 (s, 2H), 3.32 (s, 2H),2.98-3.00 (m, 1H), 1.09 (d, 6H, J=7.2 Hz). MS (ESI) m/e [M+1]⁺ 287.

Example 14 Synthesis of Compound 47 Compound 47:2-(cyclopropanecarbonyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Step 1: Methyl2-(cyclopropanecarbonyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate

To a solution of methyl4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (0.21 g,0.82 mmol) and cyclopropanecarbonyl chloride (0.074 mL, 0.82 mmol) inCH₂Cl₂ (10 mL) was added DIPEA (0.143 mL) at 0° C., and the mixture wasstirred at −5° C. for 1.0 h. Then the solvent was evaporated to give thecrude product, which was purified by Pre-TLC to give the title compound(170 mg). MS (ESI) m/e [M+1]⁺ 313.

Step 2:2-(cyclopropanecarbonyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 47 was prepared from methyl2-(cyclopropanecarbonyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylateand hydrazine hydrate according to the procedure similar to that forCompound 1. ¹H NMR (DMSO-d₆) δ 11.9 (s, 1H), 10.0 (s, 1H), 7.47-7.53 (m,2H), 7.17 (dd, 1H, J=7.2, 7.8 Hz), 4.89 (s, 2H), 4.35 (s, 2H), 2.08-2.11(m, 1H), and 0.78-0.79 (m, 4H). MS (ESI) m/e [M+1]⁺ 295.

Example 15 Synthesis of Compound 48 Compound 48:2-(cyclopropanecarbonyl)-4-(2-(dimethylamino)ethyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 48 was prepared from2-(cyclopropanecarbonyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-oneand N,N-dimethylamino-2-chloroethane according to the procedures similarto those for Compound 28. ¹H NMR (DMSO-d₆) δ 10.0 (s, 1H), 7.67 (d, 1H,J=8.4 Hz), 7.51 (d, 1H, J=7.8 Hz), 7.23 (dd, 1H, J=8.4, 7.8 Hz), 5.22(s, 1H), 4.98 (s, 1H), 4.55 (s, 1H), 4.28-4.35 (m, 3H), 2.58-2.62 (m,2H), 2.19 (s, 6H), 2.09-2.13 (m, 1H), and 0.79 (s, 4H). MS (ESI) m/e[M+1]⁺ 366.

Example 16 Synthesis of Compound 49 Compound 49:2-(cyclopropanecarbonyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 49 was prepared from methyl7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylateand cyclopropanecarbonyl chloride according to the procedures similar tothose for Compound 47. ¹H NMR (DMSO-d₆) δ 9.64 (s, 1H), 6.80-7.08 (m,2H), 4.95 (s, 1H), 4.74 (s, 1H), 4.40 (s, 1H), 4.20 (s, 1H), 2.03-2.07(m, 1H), and 0.75 (s, 4H). MS (ESI) m/e [M+1]⁺ 313.

Example 17 Synthesis of Compound 50 Compound 50:2-(Cyclopropanecarbonyl)-4-(2-(dimethylamino)ethyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 50 was prepared from2-(cyclopropanecarbonyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-oneand N,N-dimethylamino-2-chloroethane according to the procedures similarto those for Compound 28. ¹H NMR (DMSO-d₆) δ 10.0 (s, 1H), 7.66 (dd, 1H,J=2.4, 9.6 Hz), 7.26 (dd, 1H, J=2.4, 10.2 Hz), 5.21 (s, 1H), 4.96 (s,1H), 4.55 (s, 1H), 4.27-4.36 (m, 3H), 2.56-2.59 (m, 2H), 2.18 (s, 6H),2.11-2.13 (m, 1H), and 0.79 (s, 4H). MS (ESI) m/e [M+1]⁺ 384.

Example 18 Synthesis of Compound 51 Compound 51:2-Pivaloyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 51 was prepared from methyl4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate andpivaloyl chloride according to the procedures similar to those forCompound 47. ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 7.27-7.47 (m, 2H), 6.96(s, 1H), 4.89 (s, 2H), 4.33 (s, 2H), and 1.24 (s, 9H). MS (ESI) m/e[M+1]⁺ 311.

Example 19 Synthesis of Compound 52 Compound 52:6-Fluoro-2-pivaloyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 52 was prepared from methyl7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylateand pivaloyl chloride according to the procedures similar to those forCompound 47. ¹H NMR (DMSO-d₆) δ 11.9 (s, 1H), 10.2 (s, 1H), 7.45 (dd,1H, J=2.4, 9.6 Hz), 7.22 (dd, 1H, J=2.4, 10.2 Hz), 4.92 (s, 2H), 4.42(s, 2H), and 1.24 (s, 9H). MS (ESI) m/e [M+1]⁺ 329.

Example 20 Synthesis of Compound 53 Compound 53:2-Cyclohexyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 53 was prepared from methyl4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate andcyclohexanone according to the procedures similar to those for Compound44. ¹H NMR (DMSO-d₆) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.47 (d, 1H, J=7.8Hz), 7.42 (d, 1H, J=7.8 Hz), 7.12 (t, 1H, J=7.8 Hz), 3.91 (s, 2H), 3.38(s, 2H), 2.50-2.56 (m, 1H), 1.58-1.84 (m, 4H), and 1.11-1.31 (m, 6H). MS(ESI) m/e [M+1]⁺ 309.

Example 21 Synthesis of Compound 54 Compound 54:2-(3,3-dimethylbutyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 54 was prepared from2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one and3,3-dimethylbutanal according to the procedures similar to those forCompound 44. ¹H NMR (DMSO-d₆) δ 11.9 (s, 1H), 9.89 (s, 1H), 7.48 (d, 1H,J=7.8 Hz), 7.43 (d, 1H, J=7.2 Hz), 7.13 (dd, 1H, J=7.2, 7.8 Hz), 3.81(br s, 2H), 3.29 (br s, 2H), 2.57-2.58 (m, 2H), 1.43-1.46 (m, 2H), and0.91 (s, 9H). MS (ESI) m/e [M+1]⁺ 311.

Example 22 Synthesis of Compound 55 Compound 55:6-Fluoro-2-methyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 55 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoateand benzyl 3,5-dioxopiperidine-1-carboxylate according to the proceduressimilar to those for Compound 44. ¹H NMR (DMSO-d₆) δ 11.9 (s, 1H), 10.1(s, 1H), 7.36 (dd, 1H, J=1.8, 9.6 Hz), 7.20 (dd, 1H, J=1.8, 10.2 Hz),3.75 (s, 2H), 3.24 (s, 2H), 2.44 (s, 3H). MS (ESI) m/e [M+1]⁺ 259.

Example 23 Synthesis of Compound 56 Compound 56:2-Propyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 56 was prepared from methyl4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate andpropionaldehyde according to the procedures similar to those forCompound 44. ¹H NMR (DMSO-d₆) δ 11.7 (s, 1H), 9.92 (s, 1H), 7.47 (d, 1H,J=7.8 Hz), 7.43 (d, 1H, J=7.8 Hz), 7.13 (t, 1H, J=7.8 Hz), 3.81 (s, 2H),3.28 (s, 2H), 2.50-2.55 (m, 2H), 1.51-1.54 (m, 2H), and 0.89 (t, 3H,J=7.8 Hz). MS (ESI) m/e [M+1]⁺ 269.

Example 24 Synthesis of Compound 57 Compound 57:6-Fluoro-2-propyl-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 57 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoateand benzyl 3,5-dioxopiperidine-1-carboxylate according to the proceduressimilar to those for Compound 44. ¹H NMR (DMSO-d₆) δ 11.8 (s, 1H), 10.1(s, 1H), 7.36 (dd, 1H, J=1.8, 9.0 Hz), 7.19 (dd, 1H, J=1.8, 10.2 Hz),3.80 (s, 2H), 3.30 (s, 2H), 2.50-2.54 (m, 2H), 1.50-1.54 (m, 2H), and0.89 (t, 3H, J=7.8 Hz). MS (ESI) m/e [M+1]⁺ 287.

Example 25 Synthesis of Compound 58 Compound 58:2-Ethyl-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 58 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoateand benzyl 3,5-dioxopiperidine-1-carboxylate according to the proceduressimilar to those for Compound 44. ¹H NMR (DMSO-d₆) δ 11.8 (s, 1H), 10.1(s, 1H), 7.35 (dd, 1H, J=2.4, 9.6 Hz), 7.19 (dd, 1H, J=2.4, 10.2 Hz),3.80 (s, 2H), 3.30 (s, 2H), 2.60-2.64 (m, 2H), and 1.09 (t, 3H, J=7.2Hz). MS (ESI) m/e [M+1]⁺ 273.

Example 26 Synthesis of Compound 59 Compound 59:2-Butyl-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 59 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoateand benzyl 3,5-dioxopiperidine-1-carboxylate according to the proceduressimilar to those for Compound 44. ¹H NMR (DMSO-d₆) δ 11.8 (s, 1H), 10.1(s, 1H), 7.36 (dd, 1H, J=2.4, 9.6 Hz), 7.19 (dd, 1H, J=2.4, 10.2 Hz),3.80 (s, 2H), 3.30 (s, 2H), 2.54-2.57 (m, 2H), 1.47-1.50 (m, 2H),1.30-1.34 (m, 2H), and 0.91 (t, 3H, J=7.2 Hz). MS (ESI) m/e [M+1]⁺ 301.

Example 27 Synthesis of Compound 60 Compound 60:2-(2-(dimethylamino)ethyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Step 1: Methyl2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate

Methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate(183 mg, 0.75 mol) was dissolved in DMF (20 ml) and2-chloro-N,N-dimethylethanamine hydrochloride (107 mg, 0.75 mmol), andK₂CO₃ (207 mg, 1.5 mmol) were subsequently added. The reaction wasstirred at 50° C. until the starting material was disappeared. Thereaction mixture was then diluted with CH₂Cl₂ (15 ml) and washed withwater three times. The organic layer was dried with MgSO₄. Evaporationof most of the solvent and the crude product was purified bychromatography column on silica gel (elution with CH₂Cl₂/MeOH/NH₃.H₂O)to provide 0.09 g of methyl2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate.MS (ESI) m/e [M+1]⁺ 316.

Step 2:2-(2-(dimethylamino)ethyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 60 was prepared from methyl2-(2-(dimethylamino)ethyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylateand hydrazine hydrate according to the procedure similar to that forCompound 1. ¹H NMR δ 9.92 (s, 1H), 7.60 (d, 1H, J=8.4 Hz), 7.46 (d, 1H,J=7.8 Hz), 7.13 (dd, 1H, J=8.4, 7.8 Hz), 4.20-4.22 (m, 2H), 4.03 (s,2H), 3.41 (s, 2H), 2.51-2.54 (m, 2H), and 2.18 (s, 6H). MS (ESI) m/e[M+1]⁺ 298.

Example 28 Synthesis of Compound 61 Compound 61:2-(2-(Dimethylamino)ethyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 61 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoateand benzyl 3,5-dioxopiperidine-1-carboxylate according to the proceduressimilar to those for Compound 60. ¹H NMR δ 10.1 (s, 1H), 7.58 (dd, 1H,J=1.8, 10.2 Hz), 7.21 (dd, 1H, J=1.8, 10.2 Hz), 4.20-4.22 (m, 2H), 4.03(s, 2H), 3.42 (s, 2H), 2.51-2.54 (m, 2H), and 2.19 (s, 6H). MS (ESI) m/e[M+1]⁺ 316.

Example 29 Synthesis of Compound 62 Compound 62:2-(2-amino-2-methylpropanoyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Step 1: methyl2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropanoyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate

A solution of HATU (86 mg) in DMF (2 ml) was added to a mixture ofmethyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (36mg), 2-(((benzyloxy)carbonyl)amino)-2-methylpropanoic acid (21 mg),diisopropylethylamine (58) and DMF (8 ml) and the resultant mixture wasstirred at ambient temperature for 16 hours. The DMF was evaporated togive methyl2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropanoyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylatewhich was used in the next step without further purification.

Step 2:benzyl(2-methyl-1-oxo-1-(8-oxo-8,9-dihydro-2,4,9,10-tetraazacyclohepta[def]fluoren-2(1H,3H,4H)-yl)propan-2-yl)carbamate

The target product was prepared from2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropanoyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylateand hydrazine hydrate according to the procedure similar to that forCompound 1. ¹H NMR (DMSO-d₆) δ 11.8 (s, 1H), 10.2 (s, 1H), 7.18-7.55 (m,8H), 4.82-4.91 (m, 4H), 4.43-4.55 (m, 2H), 1.25 (s, 6H). MS (ESI) m/e[M+1]⁺ 446.

Step 3:2-(2-amino-2-methylpropanoyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 62 was prepared from benzyl(2-methyl-1-oxo-1-(8-oxo-8,9-dihydro-2,4,9,10-tetraazacyclohepta[def]fluoren-2(1H,3H,4H)-yl)propan-2-yl)carbamateand Pd/C (10%) according to the procedure similar to that for Compound42. ¹H NMR (DMSO-d₆) δ 11.8 (s, 1H), 9.99 (s, 1H), 7.48 (d, 1H, J=8.0Hz), 7.43 (d, 1H, J=7.2 Hz), 7.13 (dd, 1H, J=8.0, 7.2 Hz), 5.29-5.31 (m,2H), 4.69-4.75 (m, 2H), 1.26 (s, 6H). MS (ESI) m/e [M+1]⁺ 312.

Example 30 Synthesis of Compound 63 Compound 63: (5)-tert-butyl(1-oxo-1-(8-oxo-8,9-dihydro-2,4,9,10-tetraazacyclohepta[def]fluoren-2(1H,3H,4H)-yl)-3-phenylpropan-2-yl)carbamate

Compound 63 was prepared from2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one and(S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid to theprocedure similar to that for Compound 62. ¹H NMR (DMSO-d₆) δ 11.8 (s,1H), 10.0 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.05-7.47 (m, 7H), 4.96-5.02(m, 1H), 4.25-4.81 (m, 4H), 2.62-2.88 (m, 2H), 1.27 (s, 6H), and 1.16(s, 3H). MS (ESI) m/e [M+1]⁺ 474.

Example 31 Synthesis of Compound 64 Compound 64:(S)-2-(2-amino-3-phenylpropanoyl)-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 64 was prepared from Compound 63 with hydrogen chlorideaccording to the procedure similar to that for Compound 62. ¹H NMR(DMSO-d₆) δ 11.9 (s, 1H), 10.1 (s, 1H), 7.48 (d, 1H, J=8.0 Hz),7.48-7.52 (m, 2H), 7.10-7.20 (m, 6H), 4.93-4.96 (m, 3H), 4.18-4.25 (m,2H), 4.00-4.03 (m, 2H), 2.78-2.85 (m, 1H), and 2.61-2.65 (m, 1H). MS(ESI) m/e [M+1]⁺ 374.

Example 32 Synthesis of Compound 65 Compound 65:2-(2-amino-2-methylpropanoyl)-6-fluoro-2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one

Compound 65 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoateand benzyl 3,5-dioxopiperidine-1-carboxylate according to the sameprocedures similar to those for Compound 62. ¹H NMR (DMSO-d₆) δ 12.1 (s,1H), 10.2 (s, 1H), 7.40 (dd, 1H, J=1.8, 10.2 Hz), 7.20 (dd, 1H, J=1.8,10.2 Hz), 5.25 (s, 2H), 4.75 (s, 1H), and 1.32 (s, 6H). MS (ESI) m/e[M+1]⁺ 330.

Example 33 Synthesis of Compound 66 Compound 66:5,10-Bis(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

To a solution of2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one(100 mg, 0.39 mmol) in dry DMF (8 mL) was added NaH (47 mg, 1.95 mmol)under ice bath. The reaction was stirred at 0° C. for 40 minutes.2-(2-Bromoethoxy)tetrahydro-2H-pyran (194 mg, 1.17 mmol) was added tothe mixture at 0° C. and the reaction was stirred at room temperaturefor 6 hours. Then water (100 mL) was added to the mixture, extractedwith DCM (50 mL×3) and EA (50 mL×3). The organic layers were combined,washed with brine and dried over Na₂SO₄. The organic phase wasconcentrated to provide crude product. Then the crude product wasdissolved in MeOH (15 mL), p-TSA.H₂O (100 mg, 0.52 mmol) was added tothe solution and the mixture was stirred at room temperature for 16hours. Water (150 mL) was added to the mixture, extracted with EA (50mL×3). The combined organic layers were washed with saturated aqueousNaHCO₃ and brine, dried over Na₂SO₄, and concentrated The residue waspurified by Pre-TLC (DCM/MeOH=10/1) to provide 40 mg (30%) of5,10-bis(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-oneas yellow solid. ¹H NMR (DMSO-d₆) δ 7.57 (m, 2H), 7.15 (dd, 1H, J=7.2,8.4 Hz), 4.88 (t, 1H, J=5.4 Hz), 4.61 (t, 1H, J=6.0 Hz), 4.21 (t, 2H,J=5.4 Hz), 3.94 (t, 2H, J=6.6 Hz), 3.94 (t, 2H, J=6.6 Hz), 3.63-3.68 (m,2H), 2.77 (s, 2H), 2.28 (s, 2H), and 1.08 (s, 6H). MS (ESI) m/e[M+1]⁺342.2.

Example 34 Synthesis of Compound 67 Compound 67:10-(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one

To a solution of2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one(100 mg, 0.39 mmol) in dry DMF (8 mL) was added2-(2-bromoethoxy)tetrahydro-2H-pyran (194 mg, 1.17 mmol). K₂CO₃ (215 mg,1.6 mmol) was added and the mixture was heated at 70° C. for 11.5 hours.Then water (100 mL) was added to the mixture, which was then extractedwith EA (50 mL×3). The organic layers were combined, washed with brine,dried over Na₂SO₄, and concentrated to provide crude yellow oil. ThenMeOH (15 mL) was added to the residue, followed by the addition ofp-TSA.H₂O (100 mg, 0.52 mmol), and the mixture was stirred at roomtemperature for 1 hour. Water (100 mL) was added to the mixture,extracted with EA (50 mL×3). The organic layers were combined, washedwith saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, andconcentrated The residue was purified by chromatography column on silicagel (elution with hexane/ethyl acetate) to give 80 mg (69% yield) of10-(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-oneas yellow solid. ¹H NMR (DMSO-d₆) δ 9.89 (s, 1H), 7.58 (d, 1H, J=8.4Hz), 7.47 (d, 1H, J=7.2 Hz), 7.15 (dd, 1H, J=7.2, 8.4 Hz), 4.88 (t, 1H,J=5.4 Hz), 4.21 (t, 2H, J=5.4 Hz), 3.65-3.68 (m, 1H), 2.76 (s, 2H), 2.25(s, 2H), and 1.07 (s, 6H). MS (ESI) m/e [M+1]⁺298.1.

Example 35 Synthesis of Compound 68 Compound 68:(R)-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one

Step 1: (R)-methyl2-(1-(benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate

To a suspension of tetrakis(triphenylphosphine)palladium(0)(1.72 g, 1.5mmol) and CuI (0.29 g, 1.5 mmol) in 54 mL of toluene were added methyl3-amino-2-bromobenzoate (2.3 g, 10 mmol), (R)-benzyl2-ethynyl-2-methylpyrrolidine-1-carboxylate (3.0 g, 12 mmol), and TEA (7mL, 50 mmol). The mixture was stirred for 18 h at 100° C. under nitrogenatmosphere. After cooling, water (20 mL) was added. The mixture wasextracted with EtOAc (3×20 mL) and the combined organic layers werewashed with brine (20 mL) and dried over MgSO₄. The mixture wasfiltered, and the filtrate was evaporated to dryness. The residue waspurified by column chromatography on silica gel using CH₂Cl₂ as eluentto provide 2.31 g of (R)-benzyl2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate.

To a refluxing solution of (R)-benzyl2-((2-amino-6-(methoxycarbonyl)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate(1.1 g, 2.8 mmol) and dibromoethane (5.21 g, 2.8 mmol) in ethanol (20mL) was added zinc powder (1.43 g, 22 mmol) in one portion. Afterrefluxing for 8 h, the reaction mixture was filtered and the filtratewas concentrated to 3 mL, which was poured into water (15 mL). Thereaction mixture was extracted with EA (20 mL×3). The combined extractswere dried over sodium sulfate, filtered, and evaporated to give palebrown oil, which was chromatographed over silica gelelution withhexane:ethyl acetate (5:1) to give the (R)-methyl2-(1-(benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylateand (307 mg, 0.78 mmol). ¹H NMR (CDCl₃-d) δ 10.3 (s, 1H), 7.83 (d, 1H,J=7.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.29-7.35 (m, 5H), 7.16 (t, 1H, J=7.8Hz), 6.96 (s, 1H), 5.15 (s, 2H), 3.95 (s, 3H), 3.56-3.59 (m, 2H),2.83-2.85 (m, 1H), 2.03-2.07 (m, 2H), and 1.84-1.93 (m, 4H). MS (ESI)m/e [M+1]⁺ 393.0.

Step 2: (R)-methyl 2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate

A stirred mixture of (R)-methyl2-(1-(benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate(307 mg, 0.78 mol), methanol (10 mL), and 10% palladium on carbon (50mg) was treated with a balloon-pressure of hydrogen at room temperature.After 2 hours, the mixture was filtered through Celite and the filtratewas concentrated to give (R)-methyl2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (190 mg, 94%). ¹HNMR (CDCl₃-d1) δ 10.9 (s, 1H), 7.86 (d, 1H, J=7.8 Hz), 7.63 (d, 1H,J=7.8 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.14 (s, 1H), 3.96 (s, 3H), 3.40-3.43(m, 1H), 3.12-3.15 (m, 1H), 2.78-2.81 (m, 1H), 2.23-2.26 (m, 3H), and1.94 (s, 3H). MS (ESI) m/e [M+1]⁺ 259.0.

Step 3: (R)-methyl2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate

(R)-Methyl 2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (190 mg,0.74 mmol) was dissolved in CH₃CN (25 ml) and methylbromoacetate (250mg, 1.6 mmol). DIPEA (350 mg, 2.7 mmol) was then added. The reactionmixture was stirred at room temperature for about 20 hours. The reactionmixture was then diluted with CH₂Cl₂ (15 ml) and washed with water threetimes. The organic layer was dried with MgSO₄ and concentrated to give146 mg of (R)-methyl2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate.¹H NMR (CDCl₃-d) δ 7.85 (d, 1H, J=7.8 Hz), 7.13-7.29 (m, 3H), 4.92 (s,2H), 3.95 (s, 3H), 3.70 (s, 3H), 3.56-3.62 (m, 2H), 1.95-2.06 (m, 4H),and 1.94 (s, 3H). MS (ESI) m/e [M+1]⁺ 331.0.

Step 4: (R)-methyl11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate

In a 25-mL flask, (R)-methyl2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate(146 mg, 0.44 mmol) was treated with anhydrous MeSO₃H (10 mL). The flaskwas fitted with a reflux condenser and heated to 60° C. for 1 h. Then,the reaction mixture was cooled in an ice-bath and diluted withdistilled water (2.0 mL). The pH of the solution was increased to pH-10by the addition of saturated aq. NaHCO₃. The reaction mixture was thenextracted with EtOAc (3×20 mL), and the organic extracts were washedwith brine (1×20 mL), dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by flash chromatography (20 to 60% EtOAc/hexanes)to give (R)-methyl11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate(58 mg 44%). MS (ESI) m/e [M+1]⁺299.0.

Step 5:(R)-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclpenta[a]fluoren-4(5H)-one

A solution of compound (R)-methyl11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate(58 mg, 0.19 mmol), acetic acid (0.4 mL), and hydrazine hydrate (0.2 mL)in methanol (10 mL) was heated at reflux. After 7 h, the reaction wascooled and water (5 mL) was added. The mixture was extracted with EtOAc(3×5 mL) and the combined organic layers were washed with brine (10 mL)and dried over MgSO₄. The mixture was filtered, evaporated to dryness,and the residue was purified by Pre-TLC using CH₂Cl₂ as eluent to give40 mg of(R)-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.¹H NMR (DMSO-d₆) δ 12.9 (s, 1H), 10.6 (s, 1H), 7.50-7.52 (m, 2H), 7.12(t, 1H, J=7.8 Hz), 3.24-3.26 (m, 1H), 2.91 (d, 1H, J=18.4 Hz), 2.37-2.38(m, 1H), 2.30-2.32 (m, 1H), 2.20-2.21 (m, 1H), 1.95-1.96 (m, 1H),1.41-1.43 (m, 1H), 1.34 (s, 3H), and 1.18-1.19 (m 1H). MS (ESI) m/e[M+1]⁺281.0.

Example 36 Synthesis of Compound 69 Compound 69:(R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one

Step 1: Methyl 2-bromo-5-fluoro-3-(2,2,2-trifluoroacetamido)benzoate

To a solution of methyl 3-amino-2-bromo-5-fluorobenzoate (25.0 g, 100mmol) and K₂CO₃ (42.0 g, 302 mmol) in DCM (250 mL) were added2,2,2-trifluoroacetic anhydride (249.0 g, 1.197 mol) at 5-10° C. undernitrogen atmosphere. The mixture was stirred for overnight at 25° C. Thereaction mixture was diluted with DCM, washed with H₂O (200 mL×2) andsaturated NaHCO₃ aq (200 mL×2), dried over anhydrousNa₂SO₄, andconcentrated to give 34.0 g (98%) of methyl2-bromo-5-fluoro-3-(2,2,2-trifluoroacetamido)benzoate as white solid. ¹HNMR (CDCl₃-d1) δ 8.87 (s, 1H), 8.36 (d, 1H, J=6.4 Hz), 7.43 (d, 1H,J=5.2 Hz), 3.98 (s, 3H).

Step 2: (R)-benzyl2-((4-fluoro-2-(methoxycarbonyl)-6-(2,2,2trifluoroacetamido)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate

A mixture of methyl2-bromo-5-fluoro-3-(2,2,2-trifluoroacetamido)benzoate (27.52 g, 80mmol), (PPh₃)₂PdCl₂ (2.8 g, 4 mmol), (R)-benzyl2-ethynyl-2-methylpyrrolidine-1-carboxylate (19.44 g, 80 mmol),copper(I) iodide (764 mg, 4 mmol) and tetramethylguanidine (27.6 g, 240mmol) in DMF (200 mL) was heated at 80° C. with nitrogen protectionsystem for 16 hours. The cooled reaction mixture was diluted with EA(3×200 mL) and water (800 mL). The organic layer was separated, washedwith water (2×200 mL), dried (Na₂SO₄), and concentrated. The remainingresidue was chromatographed on silica gel, eluted with gradient 0-30%EtOAc in hexane to give the product (R)-benzyl2-((4-fluoro-2-(methoxycarbonyl)-6-(2,2,2trifluoroacetamido)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate(21 g, 53%) as white solid. ¹H NMR (DMSO-d1) δ 11.01 (s, 1H), 7.64-7.77(m, 1H), 7.36 (m, 5H), 7.19-7.31 (m, 1H), 5.04-5.12 (m, 2H), 3.85 (s,3H), 3.44-3.47 (m, 2H), 2.0-2.29 (m, 2H), 1.90-1.97 (m, 2H), and 1.69(s, 3H). MS (ESI) m/e [M+1]⁺ 507.0.

Step 3: (R)-methyl6-fluoro-2-(2-methyl-1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)-1H-indole-4-carboxylate

To a solution of (R)-benzyl2-((4-fluoro-2-(methoxycarbonyl)-6-(2,2,2trifluoroacetamido)phenyl)ethynyl)-2-methylpyrrolidine-1-carboxylate(5.0 g, 10 mmol) in toluene was added zinc(II) bromide (11.25 g, 50mmol) at room temperature. The reaction mixture was heated at 80° C.with nitrogen protection system for 15 hours. The solvent was removedunder reduced pressure, and the residue was treated with DCM (500 mL)and water (800 mL). The organic layer was separated, washed with water(2×200 mL), dried (Na₂SO₄), and concentrated. The remaining residue waschromatographed on silica gel, eluted with gradient 0-50% EtOAc inhexane to give the product (R)-methyl6-fluoro-2-(2-methyl-1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)-1H-indole-4-carboxylate(1.9 g, 51%) as yellow solid. ¹H NMR (CDCl₃-d1) δ 9.97 (s, 1H), 7.62 (d,1H, J=10.2 Hz), 7.27 (d, 1H, J=9.6 Hz), 7.05 (d, 1H, J=1.2 Hz), 3.98 (s,3H), 3.86-3.88 (m, 2H), 2.91-2.96 (m, 1H), 2.25-2.28 (m, 1H), 2.12-2.16(m, 2H), and 1.99 (s, 3H). MS (ESI) m/e [M+1]⁺ 507.0.

Step 4: (R)-methyl6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate

To a solution of (R)-methyl6-fluoro-2-(2-methyl-1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)-1H-indole-4-carboxylate(1.0 g, 1.9 mmol) in MeOH was added NaBH₄ (706 mg, 11.4 mmol) at roomtemperature. The reaction mixture was refluxed for 4 hours with nitrogenprotection system. The solvent was removed under reduced pressure. Theresidue was dissolved in DCM (200 mL), which was washed with water (200mL) and brine (200 mL), dried over Na₂SO₄, and concentrated to give thedesire product as yellow oil. (R)-methyl6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (727 mg,98%). ¹H NMR (CD₃OD-d1) δ 7.50 (dd, 1H, J=10.2, 2.4 Hz), 7.32 (d, 1H,J=9.0, 2.4 Hz), 6.93 (s, 1H), 3.97 (s, 3H), 3.03-3.12 (m, 2H), 2.27-2.32(m, 1H), 1.88-1.98 (m, 3H), and 1.60 (s, 3H). MS (ESI) m/e [M+1]⁺ 276.0.

Step 5: (R)-Methyl6-fluoro-2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate

To a stirred mixture of (R)-methyl6-fluoro-2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (1.0, 1.27mol), CH₃CN (50 ml) and methylbromoacetate (0.58 g, 3.82 mmol) was addedDIPEA (0.82 g, 6.35 mmol). The reaction mixture was stirred at roomtemperature for about 20 hours. The reaction mixture was then dilutedwith CH₂Cl₂ (15 ml) and washed with water three times. The organic layerwas dried with MgSO₄ and concentrated to give 0.85 g of (R)-methyl6-fluoro-2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate.¹H NMR (CD₃OD-d4) δ 7.47 (dd, 1H, J=2.4, 12.0 Hz), 7.27 (dd, 1H, J=2.4,9.0 Hz), 6.89 (s, 1H), 3.95 (s, 3H), 3.66-3.68 (m, 1H), 3.64 (s, 3H),3.16-3.17 (m, 2H), 2.72-2.75 (m, 1H), 1.88-2.02 (m, 4H), and 1.44 (s,3H). MS (ESI) m/e [M+1]⁺349.0.

Step 6: (R)-methyl9-fluoro-11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate

In a 25-mL flask, (R)-methyl6-fluoro-2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate(100 mg) was treated with anhydrous MeSO₃H (6 mL). The flask was fittedwith a reflux condenser and heated at 60° C. for 1 h. Then, the reactionmixture was cooled in an ice-bath and diluted with distilled water (6.0mL). The pH of the solution was increased to pH-10 by the addition ofsaturated aq. NaHCO₃. The reaction mixture was then extracted with EtOAc(3×5 mL). The organic extracts were combined and washed with brine (1×5mL), dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by Pre-TLC to give (R)-methyl9-fluoro-11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate(30 mg). ¹H NMR (CDCl₃-d) δ 7.14-7.224 (m, 2H), 4.03 (s, 3H), 3.81-3.84(m, 1H), 3.57-3.59 (m, 1H), 3.22-3.24 (m, 1H), 2.92-2.94 (m, 1H),2.39-2.40 (m, 1H), 2.16-2.17 (m, 1H), 1.93-1.94 (m, 1H), 1.63 (s, 3H),and 1.56-1.57 (m, 1H). MS (ESI) m/e [M+1]⁺317.0.

Step 7:(R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one

A solution of compound (R)-methyl9-fluoro-11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate(90 mg), acetic acid (0.54 g), and hydrazine hydrate (0.28 g) inmethanol (30 mL) was heated at reflux. After 5 h, the reaction wascooled and water (5 mL) was added. The mixture was extracted with EtOAc(3×5 mL). The combined organic layers were washed with brine (10 mL) anddried over MgSO₄. The mixture was filtered, and the filtrate wasevaporated to dryness, and the residue was purified by Pre-TLC usingCH₂Cl₂ as eluent to give 80 mg of(R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one.¹H NMR (DMSO-d₆) δ 11.9 (s, 1H), 10.2 (s, 1H), 7.30 (d, 1H, J=9.6 Hz),7.20 (d, 1H, J=10.2 Hz), 3.76 (d, 1H, J=16.4 Hz), 3.34 (d, 1H, J=16.4Hz), 2.99-3.02 (m, 1H), 2.54-2.58 (m, 1H), 2.35-2.40 (m, 1H), 1.90-1.94(m, 1H), 1.73-1.75 (m, 1H), 1.48 (s, 3H), and 1.43-1.45 (m, 1H). MS(ESI) m/e [M+1]⁺ 299.

Biological Activity PARP-1 Enzymatic Assay

PARP-1 enzymatic assay was conducted using a method modified from HT FHomogeneous PARP Inhibition Assay Kit (Trevigen). 8.8 nM PARP-1 waspre-incubated with different concentrations of compounds in a buffercontaining 100 mM Tris-HCl pH 8.0, 100 mM NaCl, 20 mM MgCl2, and 1% DMSOfor 30 min at RT. The auto-PARylation reaction was initiated by additionof 500 nM NAD and 20 ng/ul activated DNA (Sigma) and incubated at RT for40 min. The remaining NAD was detected by incubation with cycling assaysolution containing 1% ethanol, 0.30 U/ml alcohol dehydrogenase, 25 uMresazurin, and 0.25 U/ml diaphorase for 50 min at RT. The concentrationof NAD is proportional to the fluorescence signal at Ex540 nm/Em 590 nm.The IC₅₀s were calculated based on residual enzyme activity (the rate ofNAD decrease) in presence of increasing concentrations of compounds.

PARP-2 and PARP-3 Enzymatic Assay

PARP-2 and PARP-3 enzymatic assays were conducted using commercialPARP-2/PARP-3 Chemiluminescent Assay Kit (BPS Biosciences) and theprotocols with the kits. Briefly, histones were coated in a high bindingplate first, and incubated with PARP-2 or PARP-3, and increasingconcentrations of compounds for 0.5 h. Then, biotinylated NAD andactivated DNA were added to the wells. The biotinylated PARylationproduct was measured by adding streptavidin-HRP and HRP substrates whichproduce chemiluminescence. The IC₅₀s were calculated based on residualenzyme activity in presence of increasing concentrations of compounds.

Tankyrase-2 Enzymatic Assay

Tankyrase-2 enzymatic assay was conducted using commercial Tankyrase-2Chemiluminescent Assay Kit (BPS Biosciences) and the protocol with thekit. GST-fused tankyrase-2 (recombinant protein expressed and purifiedfrom Bacluovirus) were coated on a GSH-precoated plate first, andincubated with increasing concentrations of compounds for 0.5 h. Then,biotinylated NAD was added to the wells. The biotinylatedauto-PARylation product was measured by adding streptavidin-HRP and HRPsubstrates which produce chemiluminescence. The IC₅₀s were calculatedbased on residual enzyme activity in presence of increasingconcentrations of compounds.

PARylation Assay.

HeLa cells were seeded into a 96-wellplate with clear bottom and blackwall at an initial concentration of 5000 cells/well in culture medium(100 μL of DMEM containing 10% FBS, 0.1 mg/mL penicillin-streptomycin,and 2 mML-glutamine). The plates were incubated for 4 h at 37° C. under5% CO₂ atmosphere, and then compounds were added with serial dilutionsover eight points over a 0.01 nM-10 μM final concentration range in 0.1%DMSO/culture medium. The plate was then incubated for 18 h at 37° C. in5% CO₂. Then DNA damage was provoked by addition of 60 μL of H₂O₂solution in PBS (final concentration 200 μM). As a negative control,cells untreated with H₂O₂ were used. The plate was kept at 37° C. for 5min. Then the medium was gently removed by plate inversion, and thecells were fixed by addition of ice-cold MeOH (100 μL/well) and kept at−20° C. for 20 min. After removal of the fixative by plate inversion andwashing 10 times with PBS (120 OA the detection buffer (50 μL/well,containing PBS, Tween (0.1%), and BSA (1 mg/mL)) together with theprimary PAR mAb (Alexis ALX-804-220, 1:2000), the secondary anti-mouseAlexa Fluor 488 antibody (MolecularProbes A11029, 1:2000), and nucleardye DAPI (Molecular Probes D3571, 150 nM) were added. Followingovernight incubation at 4° C. in the dark, removal of the solution, andwashing 6 times with PBS (120 μL), the plate was read on an ArrayScanVTI (ThermoFisher). Monitoring for PAR polymer was by detection ofAlexa488 at XF100_485_20, exposure time of 0.05 s, and identification ofthe nuclei was by tracking DAPI with XF100_386_23, exposure time of 0.01s. The mean of total intensity of cells was calculated by measuring theaverage of total intensity of nuclei over the total number ofDAPI-labeled nuclei. The EC50 was determined on the basis of theresidual enzyme activity in the presence of increasing PARPiconcentration.

Compounds 1-69 as disclosed herein were tested and found to inhibitPARP, such as PARP-1, PARP-2, PARP-3, and Tankyrase-2, with IC₅₀ valuesranging from subnanomolar to 10 micromolar.

IC50s and EC50s (nM) PARP PARP-1 PARP-2 PARP-3 Tankyrase-2 PARylationCompound IC50 IC50 IC50 IC50 EC50

10 1.9 199 140 3.6

6.7 1.1 154 3.1

7.6 1.7 143 4.6

18.6 1050 46.7

6.3 1.6 164 10.1

6 1.1 80 3.9

6 0.8 102 5.5

6.5 3.5

5.2 136 203 1.7

5.8 12.4

3.3 29 2.4

25.6 26.6

19.8 77.6

5.2 0.7

6.3 0.6 832 2.9

9.1 0.7 4.8

24 15

6.0

5.2 0.7

8.9 0.5 7.3

7.0 0.3 14

15.8 75

15.2 207

>1000

>1000 >1000

11.4 0.9 4.5

11 4.4

5.5 1300 4.9

>1000 630

6.6 1500 8.1

2.9 0.2 >20000 700 3.2

190 1590

3.3 0.3 11000 2400 12

11 150 33

10 130 23

350 1510

15 22

16 30

800 2010

6.5 480 2.4

27 21 1000 2.3

16 6.9

8.5 8.0

16 24

7.1 0.8 760 1200 3.8

5.1 1.4

3.3 0.3 180 6.9

11 6.0

2.3 1.4

18 21

11 1.3 660 9.6

7.3 13.5

9.2 20

14 23

5.7 4.3

8.3 6.4

4.5 3.4

4.8 1.5

3.8 2.0

27 68.5

38 42

7.2 (2.6) 1.0 18 3800 4.0

100 235

33 48

12 2.9

1900

23 247

1.1 0.4 1220 0.6

0.9 0.5 185 766 0.6

What is claimed is:
 1. At least one compound selected from compound ofFormula (I):

stereoisomers thereof, and pharmaceutically acceptable salts thereof,wherein: R_(N) is selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylis independently optionally substituted with at least one substituentR¹²; X is selected from the group consisting of C, N, O, and S; m and n,which may be the same or different, are each an integer of 0, 1, 2, or3; t is an integer of 0, 1, 2, or 3; R¹, at each occurrence, isindependently selected from halogen, CN, NO₂, OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰,NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independentlyoptionally substituted with at least one substituent R¹²; R² is selectedfrom hydrogen, COR⁹, CONR⁹R¹⁰, CO₂R⁹, SO₂R⁹, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylis independently optionally substituted with at least one substituentR¹²; R³, R⁴, R⁵, R⁶, R⁷ and R⁸, which may be the same or different, areeach independently selected from hydrogen, halogen, —NR⁹R¹⁰, —OR⁹, oxo,—COR⁹, —CO₂R⁹, —CONR⁹R¹⁰, —NR⁹CONR¹⁰R¹¹, —NR⁹CO₂R¹⁰, —NR⁹SO₂R¹⁰, —SO₂R⁹,alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl is independently optionally substitutedwith at least one substituent R¹², or (R³ and R⁴), and/or (R⁴ and R⁵),and/or (R⁵ and R⁶), and/or (R⁶ and R⁷), and/or (R⁷ and R⁸), togetherwith the atom(s) they are attached, form a 3- to 8-membered saturated,partially or fully unsaturated ring having 0, 1 or 2 heteroatomsindependently selected from —NR¹³—, —O—, —S—, —SO— or —SO₂—, and saidring is optionally substituted with at least one substituent R¹²,provided that when X is O, R⁵ and R⁶ are absent, when X is N, R⁶ isabsent, an when X is S, R⁵ and R⁶ are absent, or at least one of R⁵ andR⁶ is oxo, when one of R³ and R⁴ is oxo, the other is absent, when oneof R⁷ and R⁸ is oxo, the other is absent, and when X is C and one of R⁵and R⁶ is oxo, the other is absent; R⁹, R¹⁰, and R¹¹, which may be thesame or different, are each selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each ofthe alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, andheteroaryl is independently optionally substituted with at least onesubstituent R¹²; R¹² is selected from CN, halogen, haloalkyl, NO₂,—NR′R″, —OR′, oxo, —COR′, —CO₂R′, —CONR′R″, —NR′CONR″R′″, —NR′CO₂R″,—NR′SO₂R″, —SO₂R′, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl, wherein R′, R″, and R′″ are independently selectedfrom hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, and heteroaryl, or (R′ and R″), and/or(R″ and R′″) together with the atoms to which they are attached, form a3- to 8-membered saturated, partially or fully unsaturated ring having0, 1 or 2 additional heteroatoms independently selected from —NR¹³—,—O—, —S—, —SO— and —SO₂—. R¹³ is selected from hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl.
 2. The at least onecompound according to claim 1, which is selected from the compounds ofFormula (II):

stereoisomers thereof, and pharmaceutically acceptable salts thereof,wherein: R_(N) is selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylis independently optionally substituted with at least one substituentR¹²; m and n, which may be the same or different, are each an integer of0, 1, 2, or 3; t is an integer of 0, 1, 2, or 3; R¹, at each occurrence,is independently selected from halogen, CN, NO₂, OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰,NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independentlyoptionally substituted with at least one substituent R¹²; R² is selectedfrom hydrogen, COR⁹, CONR⁹R¹⁰, CO₂R⁹, SO₂R⁹, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylis independently optionally substituted with at least one substituentR¹²; R³, R⁴, R⁵, R⁶, R⁷ and R⁸, which may be the same or different, areeach independently selected from hydrogen, halogen, —NR⁹R¹⁰, —OR⁹, oxo,—COR⁹, —CO₂R⁹, —CONR⁹R¹⁰, —NR⁹CONR¹⁰R¹¹, —NR⁹CO₂R¹⁰, —NR⁹SO₂R¹⁰, —SO₂R⁹,alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl is independently optionally substitutedwith at least one substituent R¹², or (R³ and R⁴), and/or (R⁴ and R⁵),and/or (R⁵ and R⁶), and/or (R⁶ and R⁷), and/or (R⁷ and R⁸), togetherwith the atom(s) to which they are attached, form a 3- to 8-memberedsaturated, partially or fully unsaturated ring having 0, 1 or 2heteroatoms independently selected from —NR¹³—, —O—, —S—, —SO— and—SO₂—, and said ring is optionally substituted with at least onesubstituent R¹², provided that when one of R³ and R⁴ is oxo, the otheris absent, when one of R⁷ and R⁸ is oxo, the other is absent, and whenone of R⁵ and R⁶ is oxo, the other is absent; R⁹, R¹⁰, and R¹¹, whichmay be the same or different, are each selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, and heteroaryl is independently optionally substituted with atleast one substituent R¹²; R¹² is selected from CN, halogen, haloalkyl,NO₂, —NR′R″, —OR′, oxo, —COR′, —CO₂R′, —CONR′R″, —NR′CONR″R′″,—NR′CO₂R″, —NR′SO₂R″, —SO₂R′, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl, wherein R′, R″, and R′″ areindependently selected from hydrogen, haloalkyl, alkyl, arylalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or (R′and R″), and/or (R″ and R′″) together with the atoms to which they areattached, form a 3- to 8-membered saturated, partially or fullyunsaturated ring having 0, 1 or 2 additional heteroatoms independentlyselected from —NR¹³—, —O—, —S—, —SO— or —SO₂—. R¹³ is selected fromhydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.
 3. Theat least one compound according to claim 1, which is selected from thecompounds of Formula (III):

stereoisomers thereof, and pharmaceutically acceptable salts thereof,wherein: R_(N) is selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylis independently optionally substituted with at least one substituentR¹²; m and n, which may be the same or different, are each an integer of0, 1, 2, or 3; t is an integer of 0, 1, 2, or 3; R¹, at each occurrence,is independently selected from halogen, CN, NO₂, OR⁹, NR⁹R¹⁰, NR⁹COR¹⁰,NR⁹SO₂R¹⁰, CONR⁹R¹⁰, COOR⁹, SO₂R⁹, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independentlyoptionally substituted with at least one substituent R¹²; R² is selectedfrom hydrogen, COR⁹, CONR⁹R¹⁰, CO₂R⁹, SO₂R⁹, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylis independently optionally substituted with at least one substituentR¹²; R³, R⁴, R⁵, R⁷ and R⁸, which may be the same or different, are eachindependently selected from hydrogen, halogen, —NR⁹R¹⁰, —OR⁹, oxo,—COR⁹, —CO₂R⁹, —CONR⁹R¹⁰, —NR⁹CONR¹⁰R¹¹, —NR⁹CO₂R¹⁰, —NR⁹SO₂R¹⁰, —SO₂R⁹,alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, and heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocyclyl, and heteroaryl is independently optionally substitutedwith at least one substituent R¹², or (R³ and R⁴), and/or (R⁴ and R⁵),and/or (R⁵ and R⁷), and/or (R⁷ and R⁸), together with the atom(s) theyare attached, form a 3- to 8-membered saturated, partially or fullyunsaturated ring having 0, 1 or 2 heteroatoms independently selectedfrom —NR¹³—, —O—, —S—, —SO—, and —SO₂—, and said ring is optionallysubstituted with at least one substituent R¹², provided that when one ofR³ and R⁴ is oxo, the other is absent, and when one of R⁷ and R⁸ is oxo,the other is absent; R⁹, R¹⁰, and R¹¹, which may be the same ordifferent, are each selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of thealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylis independently optionally substituted with at least one substituentR¹²; R¹² is selected from CN, halogen, haloalkyl, NO₂, —NR′R″, —OR′,oxo, —COR′, —CO₂R′, —CONR′R″, —NR′CONR″R′″, —NR′CO₂R″, —NR′SO₂R″,—SO₂R′, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, andheteroaryl, wherein R′, R″, and R′″ are independently selected fromhydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl, or (R′ and R″), and/or (R″ and R′″)together with the atoms to which they are attached, form a 3- to8-membered saturated, partially or fully unsaturated ring having 0, 1 or2 additional heteroatoms independently selected from —NR¹³—, —O—, —S—,—SO— or —SO₂—; and R¹³ is selected from hydrogen, alkyl, cycloalkyl,aryl, heteroaryl, and heterocyclyl.
 4. At least one compound selectedfrom the following compounds:

stereoisomers thereof, and pharmaceutically acceptable salts thereof. 5.The at least one compound of any one of claims 1-4, having aPARP-inhibiting activity corresponding to a IC₅₀ of 10 μM or less in aPARP enzyme assay.
 6. The at least one compound of any one of claims1-4, having a PARP-Pyralation activity corresponding to a EC₅₀ of 10 uMor less in a PARP cellular assay.
 7. A pharmaceutical compositioncomprising at least one pharmaceutically acceptable carrier and as anactive ingredient a therapeutically effective amount of the at least onecompound of any one of claims 1-7.
 8. A method of treating cancerresponsive to inhibition of PARP comprising administering to a subjectin recognized need thereof at least one compound of any one of claims1-4 in an amount effective to inhibit said PARP.
 9. Use of at least onecompound of any one of claims 1-4 in the manufacture of medicaments forthe treatment of at least one disease responsive to inhibition of PARP.